Method of diagnosing neoplasms

ABSTRACT

The present invention relates generally to nucleic acid molecules, the RNA and protein expression profiles of which are indicative of the onset, predisposition to the onset and/or progression of a neoplasm. More particularly, the present invention is directed to nucleic acid molecules, the expression profiles of which are indicative of the onset and/or progression of a large intestine neoplasm, such as an adenoma or an adenocarcinoma. The expression profiles of the present invention are useful in a range of applications including, but not limited to, those relating to the diagnosis and/or monitoring of colorectal neoplasms, such as colorectal adenocarcinomas. Accordingly, in a related aspect the present invention is directed to a method of screening a subject for the onset, predisposition to the onset and/or progression of a neoplasm by screening for modulation in the expression profile of one or more nucleic acid molecule markers.

FIELD OF THE INVENTION

The present invention relates generally to nucleic acid molecules, theRNA and protein expression profiles of which are indicative of theonset, predisposition to the onset and/or progression of a neoplasm.More particularly, the present invention is directed to nucleic acidmolecules, the expression profiles of which are indicative of the onsetand/or progression of a large intestine neoplasm, such as an adenoma oran adenocarcinoma. The expression profiles of the present invention areuseful in a range of applications including, but not limited to, thoserelating to the diagnosis and/or monitoring of colorectal neoplasms,such as colorectal adenocarcinomas. Accordingly, in a related aspect thepresent invention is directed to a method of screening a subject for theonset, predisposition to the onset and/or progression of a neoplasm byscreening for modulation in the expression profile of one or morenucleic acid molecule markers.

INCORPORATION BY REFERENCE OF SEQUENCE LISTING

The Sequence Listing in the ASCII text file, named as26139ABC_SeqListing.txt of 146 KB, created on November 9, 2017 andsubmitted to the United States Patent and Trademark Office via EFS-Web,is incorporated herein by reference.

BACKGROUND OF THE INVENTION

Bibliographic details of the publications referred to by author in thisspecification are collected alphabetically at the end of thedescription.

The reference in this specification to any prior publication (orinformation derived from it), or to any matter which is known, is not,and should not be taken as an acknowledgment or admission or any form ofsuggestion that that prior publication (or information derived from it)or known matter forms part of the common general knowledge in the fieldof endeavour to which this specification relates.

Adenomas are benign tumours, or neoplasms, of epithelial origin whichare derived from glandular tissue or exhibit clearly defined glandularstructures. Some adenomas show recognisable tissue elements, such asfibrous tissue (fibroadenomas) and epithelial structure, while others,such as bronchial adenomas, produce active compounds that might giverise to clinical syndromes.

Adenomas may progress to become an invasive neoplasm and are then termedadenocarcinomas. Accordingly, adenocarcinomas are defined as malignantepithelial tumours arising from glandular structures, which areconstituent parts of many organs of the body. The term adenocarcinoma isalso applied to tumours showing a glandular growth pattern. Thesetumours may be sub-classified according to the substances that theyproduce, for example mucus secreting and serous adenocarcinomas, or tothe microscopic arrangement of their cells into patterns, for examplepapillary and follicular adenocarcinomas. These carcinomas may be solidor cystic (cystadenocarcinomas). Each organ may produce tumours showinga variety of histological types, for example the ovary may produce bothmucinous and cystadenocarcinoma.

Adenomas in different organs behave differently. In general, the overallchance of carcinoma being present within an adenoma (i.e. a focus ofcancer having developed within a benign lesion) is approximately 5%.However, this is related to size of an adenoma. For instance, in thelarge bowel (colon and rectum specifically) occurrence of a cancerwithin an adenoma is rare in adenomas of less than 1 centimetre. Such adevelopment is estimated at 40 to 50% in adenomas which are greater than4 centimetres and show certain histopathological change such as villouschange, or high grade dysplasia. Adenomas with higher degrees ofdysplasia have a higher incidence of carcinoma. In any given colorectaladenoma, the predictors of the presence of cancer now or the futureoccurrence of cancer in the organ include size (especially greater than9 mm) degree of change from tubular to villous morphology, presence ofhigh grade dysplasia and the morphological change described as “serratedadenoma”. In any given individual, the additional features of increasingage, familial occurrence of colorectal adenoma or cancer, male gender ormultiplicity of adenomas, predict a future increased risk for cancer inthe organ—so-called risk factors for cancer. Except for the presence ofadenomas and its size, none of these is objectively defined and allthose other than number and size are subject to observer error and toconfusion as to precise definition of the feature in question. Becausesuch factors can be difficult to assess and define, their value aspredictors of current or future risk for cancer is imprecise.

Once a sporadic adenoma has developed, the chance of a new adenomaoccurring is approximately 30% within 26 months.

Colorectal adenomas represent a class of adenomas which are exhibitingan increasing incidence, particularly in more affluent countries. Thecauses of adenoma, and of progression to adenocarcinoma, are still thesubject of intensive research. To date it has been speculated that inaddition to genetic predisposition, environmental factors (such as diet)play a role in the development of this condition. Most studies indicatethat the relevant environmental factors relate to high dietary fat, lowfibre, low vegetable intake, smoking, obesity, physical inactivity andhigh refined carbohydrates.

Colonic adenomas are localised areas of dysplastic epithelium whichinitially involve just one or several crypts and may not protrude fromthe surface, but with increased growth in size, usually resulting froman imbalance in proliferation and/or apoptosis, they may protrude.Adenomas can be classified in several ways. One is by their grossappearance and the major descriptors include degrees of protrusion: flatsessile (i.e. protruding but without a distinct stalk) or pedunculated(i.e. having a stalk). Other gross descriptors include actual size inthe largest dimension and actual number in the colon/rectum. While smalladenomas (less than say 5 or 10 millimetres) exhibit a smooth tansurface, pedunculated and especially larger adenomas tend to have acobblestone or lobulated red-brown surface. Larger sessile adenomas mayexhibit a more delicate villous surface. Another set of descriptorsinclude the histopathological classification; the prime descriptors ofclinical value include degree of dysplasia (low or high), whether or nota focus of invasive cancer is present, degree of change from tubulargland formation to villous gland formation (hence classification istubular, villous or tubulovillous), presence of admixed hyperplasticchange and of so-called “serrated” adenomas and its subgroups. Adenomascan be situated at any site in the colon and/or rectum although theytend to be more common in the rectum and distal colon. All of thesedescriptors, with the exception of number and size, are relativelysubjective and subject to interobserver disagreement.

The various descriptive features of adenomas are of value not just toascertain the neoplastic status of any given adenomas when detected, butalso to predict a person's future risk of developing colorectal adenomasor cancer. Those features of an adenoma or number of adenomas in anindividual that point to an increased future risk for cancer orrecurrence of new adenomas include: size of the largest adenoma(especially 10 mm or larger), degree of villous change (especially atleast 25% such change and particularly 100% such change), high gradedysplasia, number (3 or more of any size or histological status) orpresence of serrated adenoma features. None except size or number isobjective and all are relatively subjective and subject to interobserverdisagreement. These predictors of risk for future neoplasia (hence“risk”) are vital in practice because they are used to determine therate and need for and frequency of future colonoscopic surveillance.More accurate risk classification might thus reduce workload ofcolonoscopy, make it more cost-effective and reduce the risk ofcomplications from unnecessary procedures.

Adenomas are generally asymptomatic, therefore rendering difficult theirdiagnosis and treatment at a stage prior to when they might developinvasive characteristics and so became cancer. It is technicallyimpossible to predict the presence or absence of carcinoma based on thegross appearance of adenomas, although larger adenomas are more likelyto show a region of malignant change than are smaller adenomas. Sessileadenomas exhibit a higher incidence of malignancy than pedunculatedadenomas of the same size. Some adenomas result in blood loss whichmight be observed or detectable in the stools; while sometimes visibleby eye, it is often, when it occurs, microscopic or “occult”. Largeradenomas tend to bleed more than smaller adenomas. However, since bloodin the stool, whether overt or occult, can also be indicative ofnon-adenomatous conditions, the accurate diagnosis of adenoma isrendered difficult without the application of highly invasive proceduressuch as colonoscopy combined with tissue acquisition by either removal(i.e. polypectomy) or biopsy and subsequent histopathological analysis.

Accordingly, there is an on-going need to elucidate the causes ofadenoma and to develop more informative diagnostic protocols or aids todiagnosis that enable one to direct colonoscopy at people more likely tohave adenomas. These adenomas may be high risk, advanced or neither ofthese. Furthermore, it can be difficult after colonoscopy to be certainthat all adenomas have been removed, especially in a person who has hadmultiple adenomas. An accurate screening test may minimise the need toundertake an early second colonoscopy to ensure that the colon has beencleared of neoplasms. Accordingly, the identification of molecularmarkers for adenomas would provide means for understanding the cause ofadenomas and cancer, improving diagnosis of adenomas includingdevelopment of useful screening tests, elucidating the histologicalstage of an adenoma, characterising a patient's future risk forcolorectal neoplasia on the basis of the molecular state of an adenomaand facilitating treatment of adenomas.

To date, research has focused on the identification of gene mutationswhich lead to the development of colorectal neoplasms. In work leadingup to the present invention, however, it has been determined thatchanges in expression profiles of genes which are also expressed inhealthy individuals are indicative of the development of neoplasms ofthe large intestine, such as adenomas and adenocarcinomas. It has beenfurther determined that in relation to neoplasms of the large intestine,diagnosis can be made based on screening for one or more of a panel ofthese differentially expressed genes. In a related aspect, it has stillfurther been determined that to the extent that neoplastic tissue hasbeen identified either by the method of the invention or by some othermethod, the present invention provides still further means ofcharacterising that tissue as an adenoma or a cancer. In yet anotheraspect, it has been determined that a proportion of these genes arecharacterised by gene expression which occurs in the context of aneoplastic state but not in the context of a non-neoplastic state,thereby facilitating the development of qualitative analyses which donot require a relative analysis to be performed against a non-neoplasticor normal control reference level. Accordingly, the inventors haveidentified a panel of genes which facilitate the diagnosis ofadenocarcinoma and adenoma development and/or the monitoring ofconditions characterised by the development of these types of neoplasms.

SUMMARY OF THE INVENTION

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

As used herein, the term “derived from” shall be taken to indicate thata particular integer or group of integers has originated from thespecies specified, but has not necessarily been obtained directly fromthe specified source. Further, as used herein the singular forms of “a”,“and” and “the” include plural referents unless the context clearlydictates otherwise.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs.

The subject specification contains amino acid and nucleotide sequenceinformation prepared using the programme PatentIn Version 3.4, presentedherein after the bibliography. Each amino acid and nucleotide sequenceis identified in the sequence listing by the numeric indicator <210 >followed by the sequence identifier (eg. <210>1, <210>2, etc). Thelength, type of sequence (amino acid, DNA, etc.) and source organism foreach sequence is indicated by information provided in the numericindicator fields <211>m <212> and <213>, respectively. Amino acid andnucleotide sequences referred to in the specification are identified bythe indicator SEQ ID NO: followed by the sequence identifier (eg. SEQ IDNO:1, SEQ ID NO: 2, etc). The sequence identifier referred to in thespecification correlates to the information provided in numericindicator field <400> in the sequence listing, which is followed by thesequence identifier (eg. <400>1, <400>2, etc). That is SEQ ID NO: 1 asdetailed in the specification correlates to the sequence indicated as<400>1 in the sequence listing.

One aspect of the present invention is directed to a method of screeningfor the onset or predisposition to the onset of a large intestineneoplasm in an individual, said method comprising measuring the level ofexpression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i)201328_at 221577_x_at 205828_at 201341_at 221922_at 205886_at 201416_at60474_at 205890_s_at 201417_at 222696_at 205910_s_at 201468_s_at223447_at 205941_s_at 201506_at 223970_at 206224_at 201563_at 225541_at206976_s_at 201656_at 225835_at 207173_x_at 201925_s_at 226360_at207457_s_at 201926_s_at 227174_at 208079_s_at 202286_s_at 227475_at208712_at 202718_at 228303_at 209218_at 202831_at 228653_at 209309_at202833_s_at 228754_at 209752_at 202935_s_at 228915_at 209773_s_at202936_s_at 229215_at 209774_x_at 203124_s_at 231832_at 209792_s_at203256_at 231941_s_at 209875_s_at 203313_s_at 232176_at 209955_s_at203510_at 232252_at 210052_s_at 203860_at 232481_s_at 210511_s_at203895_at 234331_s_at 210559_s_at 203896_s_at 235210_s_at 210766_s_at203961_at 235976_at 211506_s_at 203962_s_at 236894_at 212281_s_at204259_at 238017_at 212344_at 204351_at 238021_s_at 212353_at 204401_at238984_at 212354_at 204404_at 241031_at 213905_x_at 204855_at 200660_at214022_s_at 204885_s_at 200832_s_at 214974_x_at 205174_s_at 200903_s_at215091_s_at 205366_s_at 201014_s_at 217430_x_at 205470_s_at 201112_s_at217996_at 205513_at 201195_s_at 218507_at 205765_at 201261_x_at218963_s_at 205825_at 201292_at 218984_at 205927_s_at 201338_x_at219787_s_at 205983_at 201479_at 219911_s_at 206239_s_at 201577_at221729_at 206286_s_at 201601_x_at 221730_at 207158_at 201666_at221731_x_at 207850_at 202310_s_at 221923_s_at 209369_at 202311_s_at37892_at 210445_at 202404_s_at 222449_at 210519_s_at 202431_s_at222450_at 211429_s_at 202504_at 222549_at 212063_at 202779_s_at222608_s_at 212070_at 202859_x_at 223062_s_at 212190_at 202954_at224428_s_at 212531_at 202998_s_at 224646_x_at 212942_s_at 203083_at224915_x_at 213880_at 203213_at 225295_at 213975_s_at 203878_s_at225520_at 214235_at 204051_s_at 225664_at 214651_s_at 204127_at225681_at 217523_at 204170_s_at 225767_at 217867_x_at 204320_at225799_at 218086_at 204470_at 225806_at 218211_s_at 204475_at226227_x_at 218704_at 204580_at 226237_at 218796_at 204620_s_at226311_at 218872_at 204702_s_at 226777_at 219630_at 205361_s_at226835_s_at 219682_s_at 205476_at 227140_at 219727_at 205479_s_at229802_at 219955_at 205713_s_at 231766_s_at 219956_at 205815_at232151_at; and/or 200665_s_at (ii) FOXQ1 RNF43 CDCA7 LOXL2 MMP1 CCL20TDGF1 AZGP1 TCN1 CTSE MTHFD1L MYC MMP7 MSLN ANLN COMP WDR72 TIMP1 H19AURKA INHBA PCSK1 FAP PAICS COL11A1 CST1 DACH1 PUS7 GDF15 BGN VCAN ZNRF3CTHRC1 AXIN2 SQLE CCND1 COL1A1 MET REG3A CSE1L LGR5 SOX9 TESC PFDN4DUSP27 TMEPAI UBE2C C20orf42 SERPINB5 CDH11 TMEM97 SLC11A2 ASCL2 MMP11TRIM29 NFE2L3 SULF1 CXCL1 KLK11 CEL SLC6A6 QPCT LY6G6D NLF1 TACSTD2PDZK1IP1 SLC7A5 NPDC1 NEBL CD55 FABP6 ENC1 PCCA ECT2 SLITRK6 SERPINE2FLJ37644 COL12A1 MLPH UBE2S KRT23 L1TD1 HOXA9 TOP2A CXCL3 WDR51B TBX3CDC2 MMP3 HOXB6 BACE2 RFC3 SFRP4 FAM84A GPX2 LILRB1 UBD COL5A2 TPX2 NPM1SCD MMP12 KCNN4 RDHE2 DPEP1 SORD LOC541471 PLAU LCN2 PSAT1 CYP3A5 HSPH1PLCB4 CXCL5 ANXA3 GTF3A SPINK1 IGFBP2 CYP3A5P2 KLK10 DUOX2 TGIF1C14orf94 GPSM2 SOX4 CXCL2 RP5-875H10.1 NME1 THBS2 SLCO4A1 RPL22L1 MUC20CLDN1 CKS2 APOBEC1 RPESP REG1B PHLDA1 HIG2 RRM2 CDH3 SERPINA1 COL10A1DKC1 SPARC COL1A2 AHCY CD44 IL8in a biological sample from said individual wherein a higher level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to control levels is indicative of a neoplastic large intestinecell or a cell predisposed to the onset of a neoplastic state.

In another aspect there is provided a method of screening for the onsetor predisposition to the onset of a large intestine neoplasm in anindividual, said method comprising measuring the level of expression ofone or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:        -   225681_at; 227140_at; and/or    -   (ii) CTHRC1        in a biological sample from said individual wherein a higher        level of expression of the genes or transcripts of group (i)        and/or group (ii) relative to control levels is indicative of a        neoplastic large intestine cell or a cell predisposed to the        onset of a neoplastic state.

In yet another aspect there is provided a method of screening for theonset or predisposition to the onset of a large intestine neoplasm in anindividual, said method comprising measuring the level of expression ofone or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:        -   227475_at        -   204475_at        -   202859_x_at        -   202404_s_at; and/or    -   (ii) FOXQ1, MMP1, IL8, COL1A2        in a biological sample from said individual wherein a higher        level of expression of the genes or transcripts of group (i)        and/or group (ii) relative to control levels is indicative of a        neoplastic large intestine cell or a cell predisposed to the        onset of a neoplastic state.

In still another aspect there is provided a method of screening for theonset or predisposition to the onset of a large intestine neoplasm in anindividual, said method comprising measuring the level of expression ofone or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:        -   205513_at, 204259_at, 227174_at, 210511_s_at, 37892_at;            and/or    -   (ii) TCN1, MMP7, WDR72, INHBA, COL11A1        in a biological sample from said individual wherein a higher        level of expression of the genes or transcripts of group (i)        and/or group (ii) relative to control levels is indicative of a        neoplastic large intestine cell or a cell predisposed to the        onset of a neoplastic state.

Preferably, said control level is a non-neoplastic level.

In still yet another aspect there is provided a method of screening forthe onset or predisposition to the onset of a large intestine neoplasmin an individual, said method comprising measuring the level ofexpression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i)221577_x_at 212942_s_at 202310_s_at 213880_at 232252_at 204855_at229215_at 212354_at 228754_at 202286_s_at 203962_s_at 203860_at202935_s_at 218963_s_at 207850_at 205828_at 204051_s_at 205890_s_at200832_s_at 205983_at 212531_at; and/or (ii) LGR5 GDF15 COL1A1 ASCL2DUSP27 SERPINB5 TACSTD2 SULF1 SLC6A6 FLJ37644 NEBL PCCA MMP3 KRT23 CXCL3SCD SFRP4 UBD DPEP1 LCN2in a biological sample from said individual wherein a higher level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to control levels is indicative of a neoplastic large intestinecell or a cell predisposed to the onset of a neoplastic state.

In a further aspect the present invention is directed to a method ofscreening for the onset or predisposition to the onset of a largeintestine neoplasm in an individual, said method comprising measuringthe level of expression of one or more genes or transcripts selectedfrom:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i)201328_at 205825_at 219956_at 201468_s_at 205927_s_at 221922_at201656_at 206239_s_at 223447_at 201925_s_at 207158_at 223970_at201926_s_at 210445_at 225835_at 202718_at 210519_s_at 226360_at202831_at 211429_s_at 228303_at 202833_s_at 212063_at 228653_at203124_s_at 213975_s_at 228915_at 203313_s_at 214235_at 231832_at203860_at 214651_s_at 231941_s_at 203895_at 217523_at 232176_at203896_s_at 217867_x_at 232481_s_at 204401_at 218086_at 234331_s_at204885_s_at 218211_s_at 235210_s_at 205174_s_at 218796_at 235976_at205366_s_at 219630_at 236894_at 205470_s_at 219682_s_at 238017_at205513_at 219727_at 238984_at 205765_at 219955_at; 241031_at; and/or(ii) APOBEC1 HOXB6 QPCT BACE2 IGFBP2 RDHE2 C20orf42 ITGA6 REG4 CD44KCNN4 RETNLB CD55 KLK11 RP5-875H10.1 CTSE L1TD1 RPESP CYP3A5 LILRB1SERPINA1 CYP3A5P2 MLPH SLC11A2 DACH1 MSLN SLC12A2 DUOX2 MUC20 SLITRK6ETS2 NLF1 SPINK1 FABP6 NPDC1 TBX3 FAM84A NQO1 TCN1 GALNT6 PCCA TGIF1GPSM2 PCSK1 WDR51B GPX2 PDZK1IP1 ZNRF3 HOXA9 PLCB4in a biological sample from said individual wherein a higher level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to control levels is indicative of an adenoma cell or a cellpredisposed to the onset of an adenoma state.

In another further aspect of the present invention there is provided amethod of screening for the onset or predisposition to the onset of alarge intestine neoplasm in an individual, said method comprisingmeasuring the level of expression of one or more genes or transcriptsselected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i)200660_at 205476_at 217430_x_at 200665_s_at 205479_s_at 217996_at200832_s_at 205713_s_at 218507_at 200903_s_at 205815_at 218963_s_at201014_s_at 205828_at 218984_at 201112_s_at 205886_at 219787_s_at201195_s_at 205890_s_at 219911_s_at 201261_x_at 205910_s_at 221729_at201292_at 205941_s_at 221730_at 201338_x_at 206224_at 221731_x_at201479_at 206976_s_at 221923_s_at 201577_at 207173_x_at 37892_at201601_x_at 207457_s_at 222449_at 201666_at 208079_s_at 222450_at202310_s_at 208712_at 222549_at 202311_s_at 209218_at 222608_s_at202403_s_at 209309_at 223062_s_at 202404_s_at 209752_at 224428_s_at202431_s_at 209773_s_at 224646_x_at 202504_at 209774_x_at 224915_x_at202779_s_at 209792_s_at 225295_at 202859_x_at 209875_s_at 225520_at202954_at 209955_s_at 225664_at 202998_s_at 210052_s_at 225681_at203083_at 210511_s_at 225767_at 203213_at 210559_s_at 225799_at203878_s_at 210766_s_at 225806_at 204051_s_at 211506_s_at 226227_x_at204127_at 212281_s_at 226237_at 204170_s_at 212344_at 226311_at204320_at 212353_at 226777_at 204470_at 212354_at 226835_s_at 204475_at213905_x_at 227140_at 204580_at 214022_s_at 229802_at 204620_s_at214974_x_at 231766_s_at 204702_s_at 215091_s_at; 232151_at; and/or205361_s_at (ii) AHCY DKC1 PSAT1 ANLN ECT2 PUS7 AURKA FAP REG1A AZGP1GTF3A REG1B BGN H19 REG3A C14orf94 HIG2 RFC3 C20orf199 HSPH1 RRM2 CCL20IFITM1 S100A11 CCND1 IL8 SCD CDC2 INHBA SFRP4 CDCA7 KLK10 SLC39A10 CDH11KRT23 SLC7A5 CEL LOC541471 SLCO4A1 CKS2 LOXL2 SPARC CLDN1 LY6G6D SPP1COL10A1 MMP1 SQLE COL11A1 MMP11 SULF1 COL12A1 MMP12 THBS2 COL1A1 MMP3TIMP1 COL1A2 MTHFD1L TMEM97 COL5A2 MYC TMEPAI COL8A1 NFE2L3 TOP2A COMPNME1 TPX2 CSE1L NPM1 TRIM29 CST1 PAICS UBD CTHRC1 PFDN4 UBE2C CXCL1PHLDA1 UBE2S CXCL2 PLAU VCAN CXCL5in a biological sample from said individual wherein a higher level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to control levels is indicative of a cancer cell or a cellpredisposed to the onset of a cancerous state.

In yet another further aspect there is provided a method of screeningfor the onset or predisposition to the onset of a large intestineneoplasm in an individual, said method comprising measuring the level ofexpression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i)202286_s_at 235976_at 209309_at 204259_at 236894_at 211506_s_at204885_s_at 214974_x_at 205174_s_at 238984_at 219787_s_at 205825_at241031_at 37892_at 207850_at 202311_s_at 222608_s_at 213880_at 204320_at223062_s_at 217523_at 204475_at 225806_at 227174_at 204702_s_at226237_at 228915_at 205910_s_at 227140_at 232252_at 206224_at 229802_at;and/or (ii) MMP1 PCSK1 ANLN MMP7 CST1 DACH1 LGR5 QPCT COL11A1 WDR72 ECT2C14orf94 COL11A1 SLITRK6 AZGP1 COL1A1 L1TD1 REG4 DUSP27 KIAA1199 NFE2L3NLF1 PSAT1 CEL IL8 CXCL5 CD44 TACSTD2 CXCL3 COL8A1 MSLNin a biological sample from said individual wherein a higher level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to background levels is indicative of a neoplastic cell or acell predisposed to the onset of a neoplastic state.

Yet another aspect of the present invention provides a method ofscreening for the onset or predisposition to the onset of a largeintestine neoplasm in an individual, said method comprising measuringthe level of expression of one or more genes or transcripts selectedfrom:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs:204885_s_at 217523_at 236894_at 205174_s_at 228915_at 238984_at205825_at 235976_at 241031_at; and/or (ii) CD44 MSLN QPCT DACH1 NLF1REG4 L1TD1 PCSK1 SLITRK6in a biological sample from said individual wherein a higher level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to background levels is indicative of an adenoma cell or a cellpredisposed to the onset of an adenoma state.

In yet still another aspect there is provided a method of screening forthe onset or predisposition to the onset of a large intestine neoplasmin an individual, said method comprising measuring the level ofexpression of one or more genes or transcripts selected from:

(i) the gene, or genes detected by Affymetrix probeset IDs: 202311_s_at209309_at 223062_s_at 204320_at 211506_s_at 225806_at 204475_at214974_x_at 226237_at 204702_s_at 219787_s_at 227140_at 205910_s_at37892_at 229802_at; and/or 206224_at 222608_s_at (ii) ANLN COL1A1 IL8AZGP1 COL8A1 MMP1 C14orf94 CST1 NFE2L3 CEL CXCL5 PSAT1 COL11A1 ECT2in a biological sample from said individual wherein a higher level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to background levels is indicative of a cancer cell or a cellpredisposed to the onset of a cancerous state.

In still yet another aspect of the present invention, there is provideda method of characterising a neoplastic cell or cellular population,which cell or cellular population is derived from the large intestine ofan individual, said method comprising measuring the level of expressionof one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs:200884_at 214234_s_at 226248_s_at 203240_at 214235_at 226302_at203963_at 214433_s_at 227676_at 204508_s_at 215125_s_at 227719_at204607_at 215867_x_at 227725_at 204811_s_at 217109_at 228232_s_at204895_x_at 217110_s_at 229070_at 204897_at 218211_s_at 231832_at205259_at 219543_at 232176_at 205765_at 219955_at 232481_s_at205927_s_at 221841_s_at 235976_at 208063_s_at 221874_at 236894_at208937_s_at 223969_s_at 237521_x_at 210107_at 223970_at 242601_at213106_at; and/or (ii) CLCA1 CTSE ATP8B1 FCGBP C6orf105 CACNA2D2 HMGCS2CKB KLF4 RETNLB ATP8A1 CYP3A5P2 L1TD1 MUC4 CAPN9 SLITRK6 UGT1A1 NR3C2VSIG2 SELENBP1 PBLD LOC253012 PTGER4 CA12 ST6GALNAC1 MLPH WDR51B ID1KIAA1324 FAM3D CYP3A5in said cell or cellular population wherein a higher level of expressionof the genes or transcripts of group (i) and/or group (ii) relative to agastrointestinal cancer cell level is indicative of an adenoma cell or acell predisposed to the onset of an adenoma state.

In another aspect there is provided a method of characterising aneoplastic cell or cellular population, which cell or cellularpopulation is derived from the large intestine of an individual, saidmethod comprising measuring the level of expression of one or more genesor transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs:200600_at 204006_s_at 213428_s_at 200665_s_at 204051_s_at 213524_s_at200832_s_at 204122_at 213869_x_at 200974_at 204320_at 213905_x_at200986_at 204475_at 214247_s_at 201058_s_at 204620_s_at 215049_x_at201069_at 205479_s_at 215076_s_at 201105_at 205547_s_at 215646_s_at201141_at 205828_at 216442_x_at 201147_s_at 207173_x_at 217430_x_at201150_s_at 207191_s_at 217762_s_at 201162_at 208747_s_at 217763_s_at201163_s_at 208782_at 217764_s_at 201185_at 208788_at 218468_s_at201261_x_at 208850_s_at 218469_at 201289_at 208851_s_at 218559_s_at201426_s_at 209101_at 218638_s_at 201438_at 209156_s_at 219087_at201616_s_at 209218_at 221011_s_at 201645_at 209395_at 221729_at201667_at 209396_s_at 221730_at 201744_s_at 209596_at 221731_x_at201792_at 209875_s_at 37892_at 201842_s_at 209955_s_at 223122_s_at201852_x_at 210095_s_at 223235_s_at 201859_at 210495_x_at 224560_at201893_x_at 210511_s_at 224694_at 202237_at 210764_s_at 224724_at202238_s_at 210809_s_at 225664_at 202283_at 211161_s_at 225681_at202291_s_at 211571_s_at 225710_at 202310_s_at 211719_x_at 225799_at202311_s_at 211813_x_at 226237_at 202403_s_at 211896_s_at 226311_at202404_s_at 211959_at 226694_at 202450_s_at 211964_at 226777_at202620_s_at 211966_at 226930_at 202766_s_at 211980_at 227099_s_at202859_x_at 211981_at 227140_at 202878_s_at 212077_at 227566_at202917_s_at 212344_at 229218_at 202998_s_at 212353_at 229802_at203083_at 212354_at 231579_s_at 203325_s_at 212464_s_at 231766_s_at203382_s_at 212488_at 231879_at 203477_at 212489_at 232458_at 203570_at212667_at 233555_s_at 203645_s_at 213125_at 234994_at 203878_s_at;and/or (ii) COL1A2 LGALS1 SRGN CTHRC1 ELOVL5 LBH FN1 MGP CTGF POSTN MMP2TNC SPP1 LOXL2 G0S2 MMP1 MYL9 SQLE SPARC DCN EFEMP1 LUM CALD1 APOE GREM1FBN1 MSN IL8 MMP3 IGFBP3 IGFBP5 IGFBP7 SERPINF1 SFRP2 FSTL1 ISLR SULF1COL4A2 HNT ASPN VCAN COL5A1 COL6A3 SMOC2 OLFML2B COL8A1 HTRA1 KIAA1913COL12A1 CYR61 PALM2-AKAP2 COL5A2 FAP SERPING1 CDH11 VIM TYROBP THBS2TIMP2 ACTA2 COL15A1 SCD COL3A1 COL11A1 TIMP3 PLOD2 S100A8 AEBP1 MMP11FNDC1 GJA1 CD163 SFRP4 NNMT FCGR3B INHBA COL1A1 PLAU COL6A2 SULF2 MAFBANTXR1 COL6A1 LOC541471 GPNMB SPON2 LOC387763 BGN CTSK CHI3L1 TAGLNMXRA5 THY1 COL4A1 C1S LOXL1 RAB31 DKK3 CD93in a biological sample from said individual wherein a higher level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to a gastrointestinal adenoma cell level is indicative of acancer or a cell predisposed to the onset of a cancerous state.

In a further aspect there is provided a method of characterising aneoplastic cell or cellular population, which cell or cellularpopulation is derived from the large intestine of an individual, saidmethod comprising measuring the level of expression of one or more genesor transcripts selected from:

-   -   (i) the gene or genes detected by Affymetrix probeset IDs:        -   210107_at; and/or    -   (ii) CLCA1        in a biological sample from said individual wherein a higher        level of expression of the genes or transcripts of group (i)        and/or group (ii) relative to a gastrointestinal cancer control        level is indicative of an adenoma cell or a cell predisposed to        the onset of an adenoma state.

In another aspect there is provided a method of characterising aneoplastic cell or cellular population, which cell or cellularpopulation is derived from the large intestine of an individual, saidmethod comprising measuring the level of expression of one or more genesor transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs:203240_at 219955_at 242601_at 204607_at 232481_s_at 227725_at223969_s_at 228232_s_at; and/or (ii) FCGBP L1TD1 LOC253012 HMGCS2SLITRK6 ST6GALNAC1 RETNLB VSIG2in a biological sample from said individual wherein a higher level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to a gastrointestinal cancer control level is indicative of anadenoma cell or a cell predisposed to the onset of an adenoma state.

A further aspect of the present invention is directed to a method ofcharacterising a cell or cellular population, which cell or cellularpopulation is derived from the large intestine of an individual, saidmethod comprising measuring the level of expression of one or more genesor transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:        -   202404_s_at, 210809_s_at, 227140_at, 225681_at, 209875_s_at,            204475_at, 212464_s_at; and/or,    -   (ii) COL1A2, FN1, SPP1, CTHRC1, POSTN, MMP1        in a biological sample from said individual wherein a higher        level of expression of the genes or transcripts of group (i)        and/or (ii) relative to a gastrointestinal adenoma control level        is indicative of a cancer or a cell predisposed to the onset of        a cancerous state.

In yet another further aspect the present invention is directed to amethod of characterising a cell or cellular population, which cell orcellular population is derived from the large intestine of anindividual, said method comprising measuring the level of expression ofone or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:        -   200665_s_at, 218468_s_at, 211959_at, 201744_s_at,            202859_x_at; and/or,    -   (ii) SPARC, GREM1, IGFBP5, LUM, IL8,        in a biological sample from said individual wherein a higher        level of expression of the genes or transcripts of group (i)        and/or (ii) relative to a gastrointestinal adenoma control level        is indicative of a cancer or a cell predisposed to the onset of        a cancerous state.

In still yet another further aspect the present invention is directed toa method of characterising a cell or cellular population, which cell orcellular population is derived from the large intestine of anindividual, said method comprising measuring the level of expression ofone or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs:223122_s_at 207173_x_at 210511_s_at 212353_at 203083_at 209156_s_at219087_at 203477_at 224694_at 201438_at 37892_at 201141_at 226237_at202917_s_at 213905_x_at 225664_at 226930_at 205547_s_at 221730_at204051_s_at; and/or (ii) SFRP2 CDH11 INHBA SULF1 THBS2 COL6A2 ASPNCOL15A1 ANTXR1 COL6A3 COL11A1 GPNMB COL8A1 S100A8 BGN COL12A1 FNDC1TAGLN COL5A2 SFRP4in a biological sample from said individual wherein a higher level ofexpression of the genes or transcripts of group (i) and/or (ii) relativeto a gastrointestinal adenoma control level is indicative of a cancer ora cell predisposed to the onset of a cancerous state.

Yet another aspect of the present invention provides a method ofcharacterising a neoplastic cell or cellular population, which cell orcellular population is derived from the large intestine of anindividual, said method comprising measuring the level of expression ofone or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i)235976_at 236894_at; and/or (ii) SLITRK6 L1TD1in a biological sample from said individual wherein a higher level ofexpression of the genes or transcripts of group (i) and/or (ii) relativeto neoplastic tissue background levels is indicative of an adenoma cellor a cell predisposed to the onset of an adenoma state.

In still another aspect the present invention provides a method ofcharacterising a neoplastic cell or cellular population, which cell orcellular population is derived from the large intestine of anindividual, said method comprising measuring the level of expression ofone or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:        -   202311_s_at, 209396_s_at, 226237_at, 204320_at, 215646_s_at,            227140_at, 204475_at, 37892_at, 229802_at, 209395_at; and/or    -   (ii) COL1A1, VCAN, CHI3L1, MMP1, COL8A1, COL11A1        in a biological sample from said individual wherein a higher        level of expression of the genes or transcripts of group (i)        and/or (ii) relative to neoplastic tissue background neoplastic        cell levels is indicative of a cancer or a cell predisposed to        the onset of a cancerous state.

A related aspect of the present invention provides a molecular array,which array comprises a plurality of:

-   -   (i) nucleic acid molecules comprising a nucleotide sequence        corresponding to any one or more of the neoplastic marker genes        hereinbefore described or a sequence exhibiting at least 80%        identity thereto or a functional derivative, fragment, variant        or homologue of said nucleic acid molecule; or    -   (ii) nucleic acid molecules comprising a nucleotide sequence        capable of hybridising to any one or more of the sequences        of (i) under medium stringency conditions or a functional        derivative, fragment, variant or homologue of said nucleic acid        molecule; or    -   (iii) nucleic acid probes or oligonucleotides comprising a        nucleotide sequence capable of hybridising to any one or more of        the sequences of (i) under medium stringency conditions or a        functional derivative, fragment, variant or homologue of said        nucleic acid molecule; or    -   (iv) probes capable of binding to any one or more of the        proteins encoded by the nucleic acid molecules of (i) or a        derivative, fragment or, homologue thereof

wherein the level of expression of said marker genes of (i) or proteinsof (iv) is indicative of the neoplastic state of a cell or cellularsubpopulation derived from the large intestine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation of nuclear factor(erythroid-derived-2)-like 2. Blk=normal, grn=inflamed,red=adenoma,blue=cancer

FIG. 2 is a graphical representation of SLIT and NTRK-like family,member 6 (left) and LINE1 type transposase domain containing 1 (right).

FIG. 3 is a graphical representation of collagen type XI, alpha 1.

FIG. 4 is an image of the immunohistochemical staining for MSLN in anormal tissue shows mild staining in the cytoplasm of the colonocytes.

FIG. 5 is an image of the immunohistochemical staining for MSLN in arepresentative cancer tissue shows moderate staining in the cytoplasm ofthe colonic epithelia.

FIG. 6 is an image of the immunohistochemical staining of MSLN in amoderately differentiated adenoma shows strong staining in themultilayered colonic epithelium.

FIG. 7 is a graphical representation depicting Probeset 205828_atExpression profile across 68 clinical specimens comprising 30non-disease controls (black), 19 adenomas (red) and 19 adenocarcinoma(green).

FIG. 8 is a graphical representation of the measurement of MMP3expression in protein extract from 27 clinical stool specimens. Proteinextraction was performed on 27 clinical stool specimens comprising 6non-disease controls (circle), 10 adenoma (triangle) and 11adenocarcinoma (cross) emulsified using a PBS pH 7.4 solution containing0.05% Tween-20 and 1× Protease Inhibitor Cocktail (Roche). Proteins werefurther solubilised by 30 minutes incubation in an ultrasonic waterbath. Solubilised proteins were isolated by centrifugation andendogenous levels of MMP3 in the resulting protein extracts were usingmeasured using a commercially available Luminex bead-based suspensionimmunoassay as recommended by manufacturer (R&D Systems).

FIG. 9 is a graphical representation of Affymetrix probeset ID 205828 atwhich is known to hybrising to transcripts of the MMP3 gene depicting agene expression profile in 68 clinical specimens comprising 30non-disease controls (black), 19 adenomas (red) and 19 cancers (green).

FIG. 10 is a schematic representation of predicted RNA variants derivedfrom hCG_1815491. cDNA clones derived from map region 8579310 to 8562303on human chromosome 16 were used to locate exon sequences. Arrows: Oligonucleotide primer sets were designed to allow measurement of individualRNA variants by PCR. Primers covering splice junctions are shown asspanning intron sequences which is not included in the actualoligonucleotide primer sequence.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is predicated, in part, on the elucidation of geneexpression profiles which characterise large intestine cellularpopulations in terms of their neoplastic state and, more particularly,whether they are malignant or pre-malignant. This finding has nowfacilitated the development of routine means of screening for the onsetor predisposition to the onset of a large intestine neoplasm orcharacterising cellular populations derived from the large intestinebased on screening for upregulation of the expression of thesemolecules, relative to control expression patterns and levels. To thisend, in addition to assessing expression levels of the subject genesrelative to normal or non-neoplastic levels, it has been determined thata proportion of these genes are expressed only in the diseased state,thereby facilitating the development of a simple qualitative test basedon requiring assessment only relative to test background levels.

In accordance with the present invention, it has been determined thatthe genes detailed above are modulated, in terms of differential changesto their levels of expression, depending on whether the cell expressingthat gene is neoplastic or not. It should be understood that referenceto a gene “expression product” or “expression of a gene” is a referenceto either a transcription product (such as primary RNA or mRNA) or atranslation product such as protein. These genes and their expressionproducts, whether they be RNA transcripts or encoded proteins, arecollectively referred to as “neoplastic markers”.

Accordingly, one aspect of the present invention is directed to a methodof screening for the onset or predisposition to the onset of a largeintestine neoplasm in an individual, said method comprising measuringthe level of expression of one or more genes or transcripts selectedfrom:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs:201328_at 221577_x_at 205828_at 201341_at 221922_at 205886_at 201416_at60474_at 205890_s_at 201417_at 222696_at 205910_s_at 201468_s_at223447_at 205941_s_at 201506_at 223970_at 206224_at 201563_at 225541_at206976_s_at 201656_at 225835_at 207173_x_at 201925_s_at 226360_at207457_s_at 201926_s_at 227174_at 208079_s_at 202286_s_at 227475_at208712_at 202718_at 228303_at 209218_at 202831_at 228653_at 209309_at202833_s_at 228754_at 209752_at 202935_s_at 228915_at 209773_s_at202936_s_at 229215_at 209774_x_at 203124_s_at 231832_at 209792_s_at203256_at 231941_s_at 209875_s_at 203313_s_at 232176_at 209955_s_at203510_at 232252_at 210052_s_at 203860_at 232481_s_at 210511_s_at203895_at 234331_s_at 210559_s_at 203896_s_at 235210_s_at 210766_s_at203961_at 235976_at 211506_s_at 203962_s_at 236894_at 212281_s_at204259_at 238017_at 212344_at 204351_at 238021_s_at 212353_at 204401_at238984_at 212354_at 204404_at 241031_at 213905_x_at 204855_at 200660_at214022_s_at 204885_s_at 200832_s_at 214974_x_at 205174_s_at 200903_s_at215091_s_at 205366_s_at 201014_s_at 217430_x_at 205470_s_at 201112_s_at217996_at 205513_at 201195_s_at 218507_at 205765_at 201261_x_at218963_s_at 205825_at 201292_at 218984_at 205927_s_at 201338_x_at219787_s_at 205983_at 201479_at 219911_s_at 206239_s_at 201577_at221729_at 206286_s_at 201601_x_at 221730_at 207158_at 201666_at221731_x_at 207850_at 202310_s_at 221923_s_at 209369_at 202311_s_at37892_at 210445_at 202404_s_at 222449_at 210519_s_at 202431_s_at222450_at 211429_s_at 202504_at 222549_at 212063_at 202779_s_at222608_s_at 212070_at 202859_x_at 223062_s_at 212190_at 202954_at224428_s_at 212531_at 202998_s_at 224646_x_at 212942_s_at 203083_at224915_x_at 213880_at 203213_at 225295_at 213975_s_at 203878_s_at225520_at 214235_at 204051_s_at 225664_at 214651_s_at 204127_at225681_at 217523_at 204170_s_at 225767_at 217867_x_at 204320_at225799_at 218086_at 204470_at 225806_at 218211_s_at 204475_at226227_x_at 218704_at 204580_at 226237_at 218796_at 204620_s_at226311_at 218872_at 204702_s_at 226777_at 219630_at 205361_s_at226835_s_at 219682_s_at 205476_at 227140_at 219727_at 205479_s_at229802_at 219955_at 205713_s_at 231766_s_at 219956_at 205815_at232151_at; and/or 200665_s_at (ii) CTHRC1 CDCA7 LOXL2 FOXQ1 RNF43 TDGF1AZGP1 MMP1 CCL20 MTHFD1L MYC TCN1 CTSE ANLN COMP MMP7 MSLN H19 AURKAWDR72 TIMP1 FAP PAICS INHBA PCSK1 DACH1 PUS7 COL11A1 CST1 VCAN ZNRF3GDF15 BGN SQLE CCND1 COL1A1 AXIN2 REG3A CSE1L LGR5 MET TESC PFDN4 DUSP27SOX9 UBE2C C20orf42 SERPINB5 TMEPAI TMEM97 SLC11A2 ASCL2 CDH11 TRIM29NFE2L3 SULF1 MMP11 KLK11 CEL SLC6A6 CXCL1 LY6G6D NLF1 TACSTD2 QPCTSLC7A5 NPDC1 NEBL PDZK1IP1 FABP6 ENC1 PCCA CD55 SLITRK6 SERPINE2FLJ37644 ECT2 MLPH UBE2S KRT23 COL12A1 HOXA9 TOP2A CXCL3 L1TD1 TBX3 CDC2MMP3 WDR51B BACE2 RFC3 SFRP4 HOXB6 GPX2 LILRB1 UBD FAM84A TPX2 NPM1 SCDCOL5A2 KCNN4 RDHE2 DPEP1 MMP12 LOC541471 PLAU LCN2 SORD CYP3A5 HSPH1PLCB4 PSAT1 ANXA3 GTF3A SPINK1 CXCL5 CYP3A5P2 KLK10 DUOX2 IGFBP2C14orf94 GPSM2 SOX4 TGIF1 RP5-875H10.1 NME1 THBS2 CXCL2 RPL22L1 MUC20CLDN1 SLCO4A1 APOBEC1 RPESP REG1B CKS2 HIG2 RRM2 CDH3 PHLDA1 COL10A1DKC1 SPARC SERPINA1 AHCY CD44 COL1A2 IL8in a biological sample from said individual wherein a higher level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to control levels is indicative of a neoplastic large intestinecell or a cell predisposed to the onset of a neoplastic state.

Reference to “large intestine” should be understood as a reference to acell derived from one of the six anatomical regions of the largeintestine, which regions commence after the terminal region of theileum, these being:

-   -   (i) the cecum;    -   (ii) the ascending colon;    -   (iii) the transverse colon;    -   (iv) the descending colon;    -   (v) the sigmoid colon; and    -   (vi) the rectum.

Reference to “neoplasm” should be understood as a reference to a lesion,tumour or other encapsulated or unencapsulated mass or other form ofgrowth which comprises neoplastic cells. A “neoplastic cell” should beunderstood as a reference to a cell exhibiting abnormal growth. The term“growth” should be understood in its broadest sense and includesreference to proliferation. In this regard, an example of abnormal cellgrowth is the uncontrolled proliferation of a cell. Another example isfailed apoptosis in a cell, thus prolonging its usual life span. Theneoplastic cell may be a benign cell or a malignant cell. In a preferredembodiment, the subject neoplasm is an adenoma or an adenocarcinoma.Without limiting the present invention to any one theory or mode ofaction, an adenoma is generally a benign tumour of epithelial originwhich is either derived from epithelial tissue or exhibits clearlydefined epithelial structures. These structures may take on a glandularappearance. It can comprise a malignant cell population within theadenoma, such as occurs with the progression of a benign adenoma to amalignant adenocarcinoma.

Preferably, said neoplastic cell is an adenoma or adenocarcinoma andeven more preferably a colorectal adenoma or adenocarcinoma.

Each of the genes and transcripts detailed in sub-paragraphs (i) and(ii), above, would be well known to the person of skill in the art, aswould their encoded proteins. The identification of the expressionproducts of these genes and transcripts as markers of neoplasia occurredby virtue of differential expression analysis using Affymetrix HGU133Aor HGU133B gene chips. To this end, each gene chip is characterised byapproximately 45,000 probe sets which detect the RNA transcribed fromthe genome. On average, approximately 11 probe pairs detect overlappingor consecutive regions of the RNA transcript. In general, the genes fromwhich the RNA transcripts described herein are identified by theAffymetrix probesets are well known and characterised genes. However, tothe extent that some of the probesets detect RNA transcripts which arenot yet defined, these transcripts are indicated as “the gene, genes ortranscripts detected by Affymetrix probe x”. In some cases a number ofgenes and/or transcripts may be detectable by a single probeset. Itshould be understood, however, that this is not intended as a limitationas to how the expression level of the subject gene or transcript can bedetected. In the first instance, it would be understood that the subjectgene transcript is also detectable by other probesets which would bepresent on the Affymetrix gene chip. The reference to a single probesetsis merely included as an identifier of the gene transcript of interest.In terms of actually screening for the transcript, however, one mayutilise a probe or probeset directed to any region of the transcript andnot just to the 3′ terminal 600 bp transcript region to which theAffymetrix probesets are often directed.

Reference to each of the genes and transcripts detailed above and theirtranscribed and translated expression products should therefore beunderstood as a reference to all forms of these molecules and tofragments or variants thereof. As would be appreciated by the person ofskill in the art, some genes are known to exhibit allelic variationbetween individuals. Accordingly, the present invention should beunderstood to extend to such variants which, in terms of the presentdiagnostic applications, achieve the same outcome despite the fact thatminor genetic variants between the actual nucleic acid sequences mayexist between individuals or that within one individual there may existtwo or more splice variants of one subject gene. The present inventionshould therefore be understood to extend to all forms of RNA (eg mRNA,primary RNA transcript, miRNA, etc), cDNA and peptide isoforms whicharise from alternative splicing or any other mutation, polymorphic orallelic variation. It should also be understood to include reference toany subunit polypeptides such as precursor forms which may be generated,whether existing as a monomer, multimer, fusion protein or othercomplex.

For example, in one embodiment of the invention, the subject gene isCDH3. Analysis of the AceView Database reveals that there exist 12 CDH3alternative mRNA transcripts. Nine are generated by alternative splicingwhile three are unspliced forms. In terms of the genes encompassed bythe present invention, means for determining the existence of suchvariants and characterising same, are described in Example 6. To theextent that the genes of the present invention are described byreference to an Affymetrix probeset, Table 9 provides details of thenucleic acid sequence to which each probeset is directed. Based on thisinformation, the skilled person could, as a matter of routine procedure,identify the gene in respect of which that sequence forms part. Atypical protocol for doing this is also outlined in Example 6.

It should be understood that the “individual” who is the subject oftesting may be any human or non-human mammal. Examples of non-humanmammals includes primates, livestock animals (e.g. horses, cattle,sheep, pigs, donkeys), laboratory test animals (e.g. mice, rats,rabbits, guinea pigs), companion animals (e.g. dogs, cats) and captivewild animals (e.g. deer, foxes). Preferably the mammal is a human.

The method of the present invention is predicated on the comparison ofthe level of the neoplastic markers of a biological sample with thecontrol levels of these markers. The “control level” may be either a“normal level”, which is the level of marker expressed by acorresponding large intestine cell or cellular population which is notneoplastic, or the background level which is detectable in a negativecontrol sample.

The normal (or “non-neoplastic”) level may be determined using tissuesderived from the same individual who is the subject of testing. However,it would be appreciated that this may be quite invasive for theindividual concerned and it is therefore likely to be more convenient toanalyse the test results relative to a standard result which reflectsindividual or collective results obtained from individuals other thanthe patient in issue. This latter form of analysis is in fact thepreferred method of analysis since it enables the design of kits whichrequire the collection and analysis of a single biological sample, beinga test sample of interest. The standard results which provide the normallevel may be calculated by any suitable means which would be well knownto the person of skill in the art. For example, a population of normaltissues can be assessed in terms of the level of the neoplastic markersof the present invention, thereby providing a standard value or range ofvalues against which all future test samples are analysed. It shouldalso be understood that the normal level may be determined from thesubjects of a specific cohort and for use with respect to test samplesderived from that cohort. Accordingly, there may be determined a numberof standard values or ranges which correspond to cohorts which differ inrespect of characteristics such as age, gender, ethnicity or healthstatus. Said “normal level” may be a discrete level or a range oflevels. An increase in the expression level of the subject genesrelative to normal levels is indicative of the tissue being neoplastic.

Without limiting the present invention to any one theory or mode ofaction, although each of the genes hereinbefore described isdifferentially expressed, either singly or in combination, as betweenneoplastic versus non-neoplastic cells of the large intestine, and istherefore diagnostic of the existence of a large intestine neoplasm, theexpression of some of these genes was found to exhibit particularlysignificant levels of sensitivity, specificity and positive and negativepredictive value. Accordingly, in a preferred embodiment one wouldscreen for and assess the expression level of one or more of thesegenes. To this end, and without limiting the present invention to anyone theory or mode of action, the following markers were determined tobe expressed in neoplastic tissue at a level of 3, 4, 5 or 7 foldgreater than non-neoplastic tissue when assessed by virtue of the methodexemplified herein.

Gene, genes or transcripts detected Fold Increase by Affymetrix ProbeNo: Gene 7 225681_at CTHRC1 227140_at 5 227475_at FOXQ1 204475_at MMP1202859_x_at IL8 202404_s_at COL1A2 4 205513_at TCN1 204259_at MMP7227174_at WDR72 210511_s_at INHBA 37892_at COL11A1 3 221577_x_at GDF15202310_s_at COL1A1 213880_at LGR5 232252_at DUSP27 204855_at SERPINB5229215_at ASCL2 212354_at SULF1 228754_at SLC6A6 202286_s_at TACSTD2203962_s_at NEBL 203860_at PCCA 202935_s_at FLJ37644 218963_s_at KRT23207850_at CXCL3 205828_at MMP3 204051_s_at SFRP4 205890_s_at UBD200832_s_at SCD 205983_at DPEP1 212531_at LCN2

There is therefore more particularly provided a method of screening forthe onset or predisposition to the onset of a large intestine neoplasmin an individual, said method comprising measuring the level ofexpression of one or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:        -   225681_at; 227140_at; and/or    -   (ii) CTHRC1        in a biological sample from said individual wherein a higher        level of expression of the genes or transcripts of group (i)        and/or group (ii) relative to control levels is indicative of a        neoplastic large intestine cell or a cell predisposed to the        onset of a neoplastic state.

Preferably, said control level is a non-neoplastic level.

In another embodiment, there is provided a method of screening for theonset or predisposition to the onset of a large intestine neoplasm in anindividual, said method comprising measuring the level of expression ofone or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:        -   227475_at, 204475_at, 202859_x_at, 202404_s_at; and/or    -   (ii) FOXQ1, MMP1, IL8, COL1A2        in a biological sample from said individual wherein a higher        level of expression of the genes or transcripts of group (i)        and/or group (ii) relative to control levels is indicative of a        neoplastic large intestine cell or a cell predisposed to the        onset of a neoplastic state.

Preferably, said control level is a non-neoplastic level.

In yet another embodiment there is provided a method of screening forthe onset or predisposition to the onset of a large intestine neoplasmin an individual, said method comprising measuring the level ofexpression of one or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:        -   205513_at, 204259_at, 227174_at, 210511_s_at, 37892_at;            and/or    -   (ii) TCN1, MMP1, WDR72, INHBA, COL11A1        in a biological sample from said individual wherein a higher        level of expression of the genes or transcripts of group (i)        and/or group (ii) relative to control levels is indicative of a        neoplastic large intestine cell or a cell predisposed to the        onset of a neoplastic state.

Preferably, said control level is a non-neoplastic level.

In still yet another preferred embodiment, there is provided a method ofscreening for the onset or predisposition to the onset of a largeintestine neoplasm in an individual, said method comprising measuringthe level of expression of one or more genes or transcripts selectedfrom:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs:221577_x_at 232252_at 202310_s_at 213880_at 212354_at 204855_at229215_at 203962_s_at 228754_at 202286_s_at 218963_s_at 203860_at202935_s_at 204051_s_at 207850_at 205828_at 205983_at 205890_s_at200832_s_at 212531_at; and/or (ii) LGR5 GDF15 COL1A1 ASCL2 DUSP27SERPINB5 TACSTD2 SULF1 SLC6A6 FLJ37644 NEBL PCCA MMP3 KRT23 CXCL3 SCDSFRP4 UBD DPEP1 LCN2in a biological sample from said individual wherein a higher level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to control levels is indicative of a neoplastic large intestinecell or a cell predisposed to the onset of a neoplastic state.

Preferably, said control level is a non-neoplastic level.

According to these aspects of the present invention, said largeintestine tissue is preferably colorectal tissue.

The detection method of the present invention can be performed on anysuitable biological sample. To this end, reference to a “biologicalsample” should be understood as a reference to any sample of biologicalmaterial derived from an animal such as, but not limited to, cellularmaterial, biofluids (eg. blood), faeces, tissue biopsy specimens,surgical specimens or fluid which has been introduced into the body ofan animal and subsequently removed (such as, for example, the solutionretrieved from an enema wash). The biological sample which is testedaccording to the method of the present invention may be tested directlyor may require some form of treatment prior to testing. For example, abiopsy or surgical sample may require homogenisation prior to testing orit may require sectioning for in situ testing of the qualitativeexpression levels of individual genes. Alternatively, a cell sample mayrequire permeabilisation prior to testing. Further, to the extent thatthe biological sample is not in liquid form, (if such form is requiredfor testing) it may require the addition of a reagent, such as a buffer,to mobilise the sample.

To the extent that the neoplastic marker gene expression product ispresent in a biological sample, the biological sample may be directlytested or else all or some of the nucleic acid or protein materialpresent in the biological sample may be isolated prior to testing. Inyet another example, the sample may be partially purified or otherwiseenriched prior to analysis. For example, to the extent that a biologicalsample comprises a very diverse cell population, it may be desirable toenrich for a sub-population of particular interest. It is within thescope of the present invention for the target cell population ormolecules derived therefrom to be treated prior to testing, for example,inactivation of live virus or being run on a gel. It should also beunderstood that the biological sample may be freshly harvested or it mayhave been stored (for example by freezing) prior to testing or otherwisetreated prior to testing (such as by undergoing culturing).

The choice of what type of sample is most suitable for testing inaccordance with the method disclosed herein will be dependent on thenature of the situation. Preferably, said sample is a faecal (stool)sample, enema wash, surgical resection, tissue biopsy or blood sample.

In a related aspect, it has been determined that certain of the markershereinbefore defined are more indicative of adenoma development versuscancer development or vice versa. This is an extremely valuable findingsince it enables one to more specifically characterise the likely natureof a neoplasm which is detected by virtue of the method of the presentinvention.

Accordingly, in a related aspect the present invention is directed to amethod of screening for the onset or predisposition to the onset of alarge intestine neoplasm in an individual, said method comprisingmeasuring the level of expression of one or more genes or transcriptsselected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs:201328_at 205825_at 219956_at 201468_s_at 205927_s_at 221922_at201656_at 206239_s_at 223447_at 201925_s_at 207158_at 223970_at201926_s_at 210445_at 225835_at 202718_at 210519_s_at 226360_at202831_at 211429_s_at 228303_at 202833_s_at 212063_at 228653_at203124_s_at 213975_s_at 228915_at 203313_s_at 214235_at 231832_at203860_at 214651_s_at 231941_s_at 203895_at 217523_at 232176_at203896_s_at 217867_x_at 232481_s_at 204401_at 218086_at 234331_s_at204885_s_at 218211_s_at 235210_s_at 205174_s_at 218796_at 235976_at205366_s_at 219630_at 236894_at 205470_s_at 219682_s_at 238017_at205513_at 219727_at 238984_at 205765_at 219955_at; 241031_at; and/or(ii) APOBEC1 HOXB6 QPCT BACE2 IGFBP2 RDHE2 C20orf42 ITGA6 REG4 CD44KCNN4 RETNLB CD55 KLK11 RP5-875H10.1 CTSE L1TD1 RPESP CYP3A5 LILRB1SERPINA1 CYP3A5P2 MLPH SLC11A2 DACH1 MSLN SLC12A2 DUOX2 MUC20 SLITRK6ETS2 NLF1 SPINK1 FABP6 NPDC1 TBX3 FAM84A NQO1 TCN1 GALNT6 PCCA TGIF1GPSM2 PCSK1 WDR51B GPX2 PDZK1IP1 ZNRF3 HOXA9 PLCB4in a biological sample from said individual wherein a higher level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to control levels is indicative of an adenoma cell or a cellpredisposed to the onset of an adenoma state.

In another preferred embodiment of this aspect of the present inventionthere is provided a method of screening for the onset or predispositionto the onset of a large intestine neoplasm in an individual, said methodcomprising measuring the level of expression of one or more genes ortranscripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs:200660_at 205476_at 217430_x_at 200665_s_at 205479_s_at 217996_at200832_s_at 205713_s_at 218507_at 200903_s_at 205815_at 218963_s_at201014_s_at 205828_at 218984_at 201112_s_at 205886_at 219787_s_at201195_s_at 205890_s_at 219911_s_at 201261_x_at 205910_s_at 221729_at201292_at 205941_s_at 221730_at 201338_x_at 206224_at 221731_x_at201479_at 206976_s_at 221923_s_at 201577_at 207173_x_at 37892_at201601_x_at 207457_s_at 222449_at 201666_at 208079_s_at 222450_at202310_s_at 208712_at 222549_at 202311_s_at 209218_at 222608_s_at202403_s_at 209309_at 223062_s_at 202404_s_at 209752_at 224428_s_at202431_s_at 209773_s_at 224646_x_at 202504_at 209774_x_at 224915_x_at202779_s_at 209792_s_at 225295_at 202859_x_at 209875_s_at 225520_at202954_at 209955_s_at 225664_at 202998_s_at 210052_s_at 225681_at203083_at 210511_s_at 225767_at 203213_at 210559_s_at 225799_at203878_s_at 210766_s_at 225806_at 204051_s_at 211506_s_at 226227_x_at204127_at 212281_s_at 226237_at 204170_s_at 212344_at 226311_at204320_at 212353_at 226777_at 204470_at 212354_at 226835_s_at 204475_at213905_x_at 227140_at 204580_at 214022_s_at 229802_at 204620_s_at214974_x_at 231766_s_at 204702_s_at 215091_s_at; 232151_at; and/or205361_s_at (ii) AHCY DKC1 PSAT1 ANLN ECT2 PUS7 AURKA FAP REG1A AZGP1GTF3A REG1B BGN H19 REG3A C14orf94 HIG2 RFC3 C20orf199 HSPH1 RRM2 CCL20IFITM1 S100A11 CCND1 IL8 SCD CDC2 INHBA SFRP4 CDCA7 KLK10 SLC39A10 CDH11KRT23 SLC7A5 CEL LOC541471 SLCO4A1 CKS2 LOXL2 SPARC CLDN1 LY6G6D SPP1COL10A1 MMP1 SQLE COL11A1 MMP11 SULF1 COL12A1 MMP12 THBS2 COL1A1 MMP3TIMP1 COL1A2 MTHFD1L TMEM97 COL5A2 MYC TMEPAI COL8A1 NFE2L3 TOP2A COMPNME1 TPX2 CSE1L NPM1 TRIM29 CST1 PAICS UBD CTHRC1 PFDN4 UBE2C CXCL1PHLDA1 UBE2S CXCL2 PLAU VCAN CXCL5in a biological sample from said individual wherein a higher level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to control levels is indicative of a cancer cell or a cellpredisposed to the onset of a cancerous state.

According to these aspects, said control levels are preferablynon-neoplastic levels and said large intestine tissue is colorectaltissue. Even more preferably, said biological sample is a stool sampleor blood sample.

In a related aspect, it has been determined that a subpopulation of themarkers of the present invention are not only expressed at levels higherthan normal levels, their expression pattern is uniquely characterisedby the fact that expression levels above that of background controllevels are not detectable in non-neoplastic tissue. This determinationhas therefore enabled the development of qualitative screening systemswhich are simply designed to detect marker expression relative to acontrol background level. In accordance with this aspect of the presentinvention, said “control level” is therefore the “background level”.Preferably, said background level is of the chosen testing methodology.

According to this aspect, there is therefore provided a method ofscreening for the onset or predisposition to the onset of a largeintestine neoplasm in an individual, said method comprising measuringthe level of expression of one or more genes or transcripts selectedfrom:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs:202286_s_at 235976_at 209309_at 204259_at 236894_at 211506_s_at204885_s_at 214974_x_at 205174_s_at 238984_at 219787_s_at 205825_at241031_at 37892_at 207850_at 202311_s_at 222608_s_at 213880_at 204320_at223062_s_at 217523_at 204475_at 225806_at 227174_at 204702_s_at226237_at 228915_at 205910_s_at 227140_at 232252_at 206224_at 229802_at;and/or (ii) MMP1 PCSK1 ANLN MMP7 CST1 DACH1 LGR5 QPCT COL11A1 WDR72 ECT2C14orf94 COL11A1 SLITRK6 AZGP1 COL1A1 L1TD1 REG4 DUSP27 KIAA1199 NFE2L3NLF1 PSAT1 CEL IL8 CXCL5 CD44 TACSTD2 CXCL3 COL8A1 MSLNin a biological sample from said individual wherein a higher level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to background levels is indicative of a neoplastic cell or acell predisposed to the onset of a neoplastic state.

In a most preferred embodiment, said genes or transcripts are selectedfrom:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs:227140_at 227174_at 241031_at 204475_at 37892_at 211506_s_at 204259_at202311_s_at 202286_s_at 213880_at 232252_at 226237_at; and/or (ii) MMP1COL11A1 IL8 MMP7 COL1A1 TACSTD2 LGR5 DUSP27 COL8A1 WDR72 NLF1

Preferably, said neoplasm is an adenoma or an adenocarcinoma and saidgastrointestinal tissue is colorectal tissue.

In yet another embodiment, it has been determined that a furthersubpopulation of these markers are more characteristic of adenomadevelopment, while others are more characteristic of cancer development.Accordingly, there is provided a convenient means of qualitativelyobtaining indicative information in relation to the characteristics ofthe subject neoplasm.

According to this embodiment there is provided a method of screening forthe onset or predisposition to the onset of a large intestine neoplasmin an individual, said method comprising measuring the level ofexpression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i)204885_s_at 217523_at 236894_at 205174_s_at 228915_at 238984_at205825_at 235976_at 241031_at; and/or (ii) CD44 MSLN QPCT DACH1 NLF1REG4 L1TD1 PCSK1 SLITRK6in a biological sample from said individual wherein a higher level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to background levels is indicative of an adenoma cell or a cellpredisposed to the onset of an adenoma state.

In yet still another preferred embodiment there is provided a method ofscreening for the onset or predisposition to the onset of a largeintestine neoplasm in an individual, said method comprising measuringthe level of expression of one or more genes or transcripts selectedfrom:

the gene or genes detected by Affymetrix probeset IDs: (i) 202311_s_at209309_at 223062_s_at 204320_at 211506_s_at 225806_at 204475_at214974_x_at 226237_at 204702_s_at 219787_s_at 227140_at 205910_s_at37892_at 229802_at; and/or 206224_at 222608_s_at (ii) ANLN COL1A1 IL8AZGP1 COL8A1 MMP1 C14orf94 CST1 NFE2L3 CEL CXCL5 PSAT1 COL11A1 ECT2in a biological sample from said individual wherein a higher level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to background levels is indicative of a cancer cell or a cellpredisposed to the onset of a cancerous state.

Preferably, said large intestine tissue is colorectal tissue.

More preferably, said biological sample is a blood sample or stoolsample.

As detailed hereinbefore, the present invention is designed to screenfor a neoplastic cell or cellular population, which is located in thelarge intestine. Accordingly, reference to “cell or cellular population”should be understood as a reference to an individual cell or a group ofcells. Said group of cells may be a diffuse population of cells, a cellsuspension, an encapsulated population of cells or a population of cellswhich take the form of tissue.

Reference to “expression” should be understood as a reference to thetranscription and/or translation of a nucleic acid molecule. In thisregard, the present invention is exemplified with respect to screeningfor neoplastic marker expression products taking the form of RNAtranscripts (eg primary RNA or mRNA). Reference to “RNA” should beunderstood to encompass reference to any form of RNA, such as primaryRNA or mRNA. Without limiting the present invention in any way, themodulation of gene transcription leading to increased or decreased RNAsynthesis will also correlate with the translation of some of these RNAtranscripts (such as mRNA) to produce a protein product. Accordingly,the present invention also extends to detection methodology which isdirected to screening for modulated levels or patterns of the neoplasticmarker protein products as an indicator of the neoplastic state of acell or cellular population. Although one method is to screen for mRNAtranscripts and/or the corresponding protein product, it should beunderstood that the present invention is not limited in this regard andextends to screening for any other form of neoplastic marker expressionproduct such as, for example, a primary RNA transcript. It is wellwithin the skill of the person of skill in the art to determine the mostappropriate screening target for any given situation. To this end, thegenes which are known to encode an expression product which is eithersecreted by the cell or membrane bound is detailed in the table, below.It would be appreciated that screening for neoplastic markers which aresecreted or membrane bound may provide particular advantages in terms ofthe design of a diagnostic screening product.

The gene or genes detected by Affymetrix probe Nos: 200600_at 203961_at212077_at 224724_at 200832_s_at 203962_s_at 212281_s_at 224915_x_at200903_s_at 204006_s_at 212344_at 225295_at 200974_at 204122_at212353_at 225520_at 201058_s_at 204127_at 212354_at 225541_at 201069_at204170_s_at 212942_s_at 225664_at 201105_at 204320_at 213125_at225710_at 201112_s_at 204351_at 213524_s_at 225767_at 201195_s_at204401_at 213869_x_at 225799_at 201328_at 204404_at 213880_at 225806_at201341_at 204702_s_at 214022_s_at 225835_at 201416_at 204885_s_at214235_at 226227_x_at 201417_at 205361_s_at 214651_s_at 226311_at201426_s_at 205366_s_at 215049_x_at 226360_at 201468_s_at 205547_s_at217523_at 226694_at 201479_at 205765_at 217762_s_at 226777_at 201563_at205825_at 217763_s_at 226835_s_at 201601_x_at 205890_s_at 217764_s_at227099_s_at 201616_s_at 205927_s_at 217867_x_at 227140_at 201656_at205941_s_at 217996_at 227174_at 201667_at 205983_at 218086_at 227475_at201925_s_at 206286_s_at 218211_s_at 227566_at 201926_s_at 206976_s_at218559_s_at 228303_at 202237_at 207158_at 218704_at 228653_at202238_s_at 207173_x_at 218796_at 228754_at 202286_s_at 207191_s_at218872_at 228915_at 202431_s_at 208079_s_at 218963_s_at 229215_at202450_s_at 208712_at 218984_at 229802_at 202504_at 208782_at 219630_at231766_s_at 202620_s_at 208788_at 219682_s_at 231832_at 202779_s_at208850_s_at 219727_at 231879_at 202831_at 208851_s_at 219787_s_at232151_at 202878_s_at 209156_s_at 219911_s_at 232176_at 202917_s_at209218_at 219955_at 232252_at 202935_s_at 209369_at 219956_at232481_s_at 202936_s_at 209596_at 221011_s_at 233555_s_at 202954_at209773_s_at 221922_at 234331_s_at 203124_s_at 209955_s_at 221923_s_at234994_at 203213_at 210052_s_at 222449_at 235210_s_at 203256_at210445_at 222450_at 235976_at 203313_s_at 210519_s_at 222549_at236894_at 203382_s_at 210559_s_at 222608_s_at 238017_at 203645_s_at210766_s_at 223062_s_at 241031_at 203860_at 211964_at 223235_s_at37892_at 203878_s_at 211966_at 224428_s_at 60474_at 203895_at 212063_at224646_x_at S100A11 203896_s_at 212070_at 224694_at S100A8 ACTA2 DUOX2LOC541471 S100P AHCY DUSP27 MAFB SCD ANLN ECT2 MLPH SLC11A2 ANTXR1ELOVL5 MMP11 SLC12A2 ANXA3 ENC1 MMP2 SLC39A10 APOBEC1 ETS2 MSLN SLC6A6APOE FABP6 MSN SLC7A5 ASCL2 FAM84A MTHFD1L SLCO4A1 AURKA FAP MXRA5SLITRK6 BACE2 FCGR3B MYC SMOC2 C14orf94 FLJ37644 MYL9 SORD C20orf199FOXQ1 NEBL SOX4 C20orf42 FSTL1 NFE2L3 SOX9 CALD1 G0S2 NLF1 SQLE CCND1GALNT6 NNMT SULF1 CD163 GJA1 NPDC1 SULF2 CD44 GPR56 NPM1 TACSTD2 CD55GPSM2 NQO1 TAGLN CD93 GPX2 OLFML2B TBX3 CDC2 H19 PALM2- TDGF1 CDCA7 HNTAKAP2 TESC CDH11 HOXA9 PCCA TGIF1 CDH3 HOXB6 PCSK1 THY1 CKS2 HSPH1PDZK1IP1 TMEM97 CLDN1 IFITM1 PFDN4 TMEPAI COL10A1 ISLR PHLDA1 TPX2COL11A1 ITGA6 PLCB4 TRIM29 COL12A1 KCNN4 PLOD2 TYROBP COL4A2 KIAA1199PSAT1 UBD COL6A2 KIAA1913 PUS7 UBE2C CSE1L KRT23 RAB31 UBE2S CTSE L1TD1RDHE2 VIM CTSK LBH RFC3 WDR51B CYP3A5 LGALS1 RNF43 WDR72 CYP3A5P2 LGR5RP5-875H10.1 ZNRF3 DACH1 LOC387763 RPESP DKC1 RPL22L1 DPEP1 RRM2

Reference to “nucleic acid molecule” should be understood as a referenceto both deoxyribonucleic acid molecules and ribonucleic acid moleculesand fragments thereof. The present invention therefore extends to bothdirectly screening for mRNA levels in a biological sample or screeningfor the complementary cDNA which has been reverse-transcribed from anmRNA population of interest. It is well within the skill of the personof skill in the art to design methodology directed to screening foreither DNA or RNA. As detailed above, the method of the presentinvention also extends to screening for the protein product translatedfrom the subject mRNA.

Preferably, the level of gene expression is measured by reference togenes which encode a protein product and, more particularly, said levelof expression is measured at the protein level. Accordingly, to theextent that the present invention is directed to screening for markerswhich are detailed in the preceding table, said screening is preferablydirected to the encoded protein.

As detailed hereinbefore, it should be understood that although thepresent invention is exemplified with respect to the detection ofexpressed nucleic acid molecules (e.g. mRNA), it also encompassesmethods of detection based on screening for the protein product of thesubject genes. The present invention should also be understood toencompass methods of detection based on identifying both proteins and/ornucleic acid molecules in one or more biological samples. This may be ofparticular significance to the extent that some of the neoplasticmarkers of interest may correspond to genes or gene fragments which donot encode a protein product. Accordingly, to the extent that thisoccurs it would not be possible to test for a protein and the subjectmarker would have to be assessed on the basis of transcriptionexpression profiles.

In terms of screening for the upregulation of expression of a marker itwould also be well known to the person of skill in the art that changeswhich are detectable at the DNA level are indicative of changes to geneexpression activity and therefore changes to expression product levels.Such changes include but are not limited to, changes to DNA methylation.Accordingly, reference herein to “screening the level of expression” andcomparison of these “levels of expression” to control “levels ofexpression” should be understood as a reference to assessing DNA factorswhich are related to transcription, such as gene/DNA methylationpatterns.

The term “protein” should be understood to encompass peptides,polypeptides and proteins (including protein fragments). The protein maybe glycosylated or unglycosylated and/or may contain a range of othermolecules fused, linked, bound or otherwise associated to the proteinsuch as amino acids, lipids, carbohydrates or other peptides,polypeptides or proteins. Reference herein to a “protein” includes aprotein comprising a sequence of amino acids as well as a proteinassociated with other molecules such as amino acids, lipids,carbohydrates or other peptides, polypeptides or proteins.

The proteins encoded by the neoplastic markers of the present inventionmay be in multimeric form meaning that two or more molecules areassociated together. Where the same protein molecules are associatedtogether, the complex is a homomultimer. An example of a homomultimer isa homodimer. Where at least one marker protein is associated with atleast one non-marker protein, then the complex is a heteromultimer suchas a heterodimer.

Reference to a “fragment” should be understood as a reference to aportion of the subject nucleic acid molecule or protein. This isparticularly relevant with respect to screening for modulated RNA levelsin stool samples since the subject RNA is likely to have been degradedor otherwise fragmented due to the environment of the gut. One maytherefore actually be detecting fragments of the subject RNA molecule,which fragments are identified by virtue of the use of a suitablyspecific probe.

Reference to the “onset” of a neoplasm, such as adenoma oradenocarcinoma, should be understood as a reference to one or more cellsof that individual exhibiting dysplasia. In this regard, the adenoma oradenocarcinoma may be well developed in that a mass of dysplastic cellshas developed. Alternatively, the adenoma or adenocarcinoma may be at avery early stage in that only relatively few abnormal cell divisionshave occurred at the time of diagnosis. The present invention alsoextends to the assessment of an individual's predisposition to thedevelopment of a neoplasm, such as an adenoma or adenocarcinoma. Withoutlimiting the present invention in any way, changed levels of theneoplastic markers may be indicative of that individual's predispositionto developing a neoplasia, such as the future development of an adenomaor adenocarcinoma or another adenoma or adenocarcinoma.

In yet another related aspect of the present invention, markers havebeen identified which enable the characterisation of neoplastic tissueof the large intestine in terms of whether it is an adenoma or a cancer.This development now provides a simple yet accurate means ofcharacterising tissue using means other than the traditional methodswhich are currently utilised.

According to this aspect of the present invention, there is provided amethod of characterising a neoplastic cell or cellular population, whichcell or cellular population is derived from the large intestine of anindividual, said method comprising measuring the level of expression ofone or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i)200884_at 214234_s_at 226248_s_at 203240_at 214235_at 226302_at203963_at 214433_s_at 227676_at 204508_s_at 215125_s_at 227719_at204607_at 215867_x_at 227725_at 204811_s_at 217109_at 228232_s_at204895_x_at 217110_s_at 229070_at 204897_at 218211_s_at 231832_at205259_at 219543_at 232176_at 205765_at 219955_at 232481_s_at205927_s_at 221841_s_at 235976_at 208063_s_at 221874_at 236894_at208937_s_at 223969_s_at 237521_x_at 210107_at 223970_at 242601_at213106_at; and/or (ii) CLCA1 CTSE ATP8B1 FCGBP C6orf105 CACNA2D2 HMGCS2CKB KLF4 RETNLB ATP8A1 CYP3A5P2 L1TD1 MUC4 CAPN9 SLITRK6 UGT1A1 NR3C2VSIG2 SELENBP1 PBLD LOC253012 PTGER4 CA12 ST6GALNAC1 MLPH WDR51B ID1KIAA1324 FAM3D CYP3A5in said cell or cellular population wherein a higher level of expressionof the genes or transcripts of group (i) and/or group (ii) relative to agastrointestinal cancer cell level is indicative of an adenoma cell or acell predisposed to the onset of an adenoma state.

In another aspect there is provided a method of characterising aneoplastic cell or cellular population, which cell or cellularpopulation is derived from the large intestine of an individual, saidmethod comprising measuring the level of expression of one or more genesor transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i)200600_at 204006_s_at 213428_s_at 200665_s_at 204051_s_at 213524_s_at200832_s_at 204122_at 213869_x_at 200974_at 204320_at 213905_x_at200986_at 204475_at 214247_s_at 201058_s_at 204620_s_at 215049_x_at201069_at 205479_s_at 215076_s_at 201105_at 205547_s_at 215646_s_at201141_at 205828_at 216442_x_at 201147_s_at 207173_x_at 217430_x_at201150_s_at 207191_s_at 217762_s_at 201162_at 208747_s_at 217763_s_at201163_s_at 208782_at 217764_s_at 201185_at 208788_at 218468_s_at201261_x_at 208850_s_at 218469_at 201289_at 208851_s_at 218559_s_at201426_s_at 209101_at 218638_s_at 201438_at 209156_s_at 219087_at201616_s_at 209218_at 221011_s_at 201645_at 209395_at 221729_at201667_at 209396_s_at 221730_at 201744_s_at 209596_at 221731_x_at201792_at 209875_s_at 37892_at 201842_s_at 209955_s_at 223122_s_at201852_x_at 210095_s_at 223235_s_at 201859_at 210495_x_at 224560_at201893_x_at 210511_s_at 224694_at 202237_at 210764_s_at 224724_at202238_s_at 210809_s_at 225664_at 202283_at 211161_s_at 225681_at202291_s_at 211571_s_at 225710_at 202310_s_at 211719_x_at 225799_at202311_s_at 211813_x_at 226237_at 202403_s_at 211896_s_at 226311_at202404_s_at 211959_at 226694_at 202450_s_at 211964_at 226777_at202620_s_at 211966_at 226930_at 202766_s_at 211980_at 227099_s_at202859_x_at 211981_at 227140_at 202878_s_at 212077_at 227566_at202917_s_at 212344_at 229218_at 202998_s_at 212353_at 229802_at203083_at 212354_at 231579_s_at 203325_s_at 212464_s_at 231766_s_at203382_s_at 212488_at 231879_at 203477_at 212489_at 232458_at 203570_at212667_at 233555_s_at 203645_s_at 213125_at 234994_at 203878_s_at;and/or (ii) COL1A2 LGALS1 SRGN CTHRC1 ELOVL5 LBH FN1 MGP CTGF POSTN MMP2TNC SPP1 LOXL2 G0S2 MMP1 MYL9 SQLE SPARC DCN EFEMP1 LUM CALD1 APOE GREM1FBN1 MSN IL8 MMP3 IGFBP3 IGFBP5 IGFBP7 SERPINF1 SFRP2 FSTL1 ISLR SULF1COL4A2 HNT ASPN VCAN COL5A1 COL6A3 SMOC2 OLFML2B COL8A1 HTRA1 KIAA1913COL12A1 CYR61 PALM2-AKAP2 COL5A2 FAP SERPING1 CDH11 VIM TYROBP THBS2TIMP2 ACTA2 COL15A1 SCD COL3A1 COL11A1 TIMP3 PLOD2 S100A8 AEBP1 MMP11FNDC1 GJA1 CD163 SFRP4 NNMT FCGR3B INHBA COL1A1 PLAU COL6A2 SULF2 MAFBANTXR1 COL6A1 LOC541471 GPNMB SPON2 LOC387763 BGN CTSK CHI3L1 TAGLNMXRA5 THY1 COL4A1 C1S LOXL1 RAB31 DKK3 CD93in a biological sample from said individual wherein a higher level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to a gastrointestinal adenoma cell level is indicative of acancer or a cell predisposed to the onset of a cancerous state.

Preferably, said gastrointestinal tissue is colorectal tissue.

Reference to an “adenoma control level” or “cancer control level” shouldbe understood as a reference to the level of said gene expression in apopulation of adenoma or cancer gastrointestinal cells, respectively. Asdiscussed hereinbefore in relation to “normal levels”, the subject levelmay be a discrete level or a range of levels. Accordingly, thedefinition of “adenoma control level” or “cancer control level” shouldbe understood to have a corresponding definition to “normal level”,albeit in the context of the expression of genes by a neoplasticpopulation of large intestine cells.

In terms of this aspect of the present invention, the subject analysisis performed on a population of neoplastic cells. These cells may bederived in any manner, such as sloughed of neoplastic cells which havebeen collected via an enema wash or from a gastrointestinal sample, suchas a stool sample. Alternatively, the subject cells may have beenobtained via a biopsy or other surgical technique.

Without limiting this aspect of the invention in any way, several of themarkers of this aspect of the present invention have been determined tobe expressed at particularly significant levels above those ofneoplastic cells. For example, increased expression levels of 3- and5-fold have been observed in respect of the following markers, whenassessed by the method exemplified herein, which are indicative ofgastrointestinal adenomas.

Gene or genes detected by Fold Increase Affymetrix Probe No: Gene 5210107_at CLCA1 3 203240_at FCGBP 204607_at HMGCS2 223969_s_at RETNLB219955_at L1TD1 232481_s_at SLITRK6 228232_s_at VSIG2 242601_atLOC253012 227725_at ST6GALNAC1

In another example, increased expression levels of between 3- and 9-foldhave been observed in respect of the following markers which areindicative of gastrointestinal cancers, when assessed by the methodherein exemplified:

Gene or genes detected by Fold Increase Affymetrix Probe No: Gene 9202404_s_at COL1A2 8 225681_at CTHRC1 7 212464_s_at FN1 210809_s_atPOSTN 6 209875_s_at SPP1 5 227140_st MMP1 204475_at 4 200665_s_at SPARC201744_s_at LUM 218468_s_at GREM1 202859_x_at IL8 211959_at IGFBP5 3223122_s_at SFRP2 212353_at SULF1 219087_at ASPN 201438_at COL6A3226237_at COL8A1 225664_at COL12A1 221730_at COL5A2 207173_x_at CDH11203083_at THBS2 203477_at COL15A1 37892_at COL11A1 202917_s_at S100A8226930_at FNDC1 204051_s_at SFRP4 210511_s_at INHBA 209156_s_at COL6A2224694_at ANTXR1 201141_at GPNMB 213905_x_at BGN 205547_s_at TAGLN

According to this embodiment, there is therefore provided a method ofcharacterising a neoplastic cell or cellular population, which cell orcellular population is derived from the large intestine of anindividual, said method comprising measuring the level of expression ofone or more genes or transcripts selected from:

-   -   (i) the gene or genes detected by Affymetrix probeset IDs:        -   210107_at; and/or    -   (ii) CLCA1        in a biological sample from said individual wherein a higher        level of expression of the genes or transcripts of group (i)        and/or group (ii) relative to a gastrointestinal cancer control        level is indicative of an adenoma cell or a cell predisposed to        the onset of an adenoma state.

In another embodiment, there is provided a method of characterising aneoplastic cell or cellular population, which cell or cellularpopulation is derived from the large intestine of an individual, saidmethod comprising measuring the level of expression of one or more genesor transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i)203240_at 219955_at 242601_at 204607_at 232481_s_at 227725_at223969_s_at 228232_s_at; and/or (ii) FCGBP L1TD1 LOC253012 HMGCS2SLITRK6 ST6GALNAC1 RETNLB VSIG2in a biological sample from said individual wherein a higher level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to a gastrointestinal cancer control level is indicative of anadenoma cell or a cell predisposed to the onset of an adenoma state.

Preferably, said gastrointestinal tissue is colorectal tissue.

Still more preferably, said biological sample is a tissue sample.

In another preferred embodiment the present invention is directed to amethod of characterising a cell or cellular population, which cell orcellular population is derived from the large intestine of anindividual, said method comprising measuring the level of expression ofone or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i)202404_s_at 210809_s_at 227140_at 225681_at 209875_s_at 204475_at212464_s_at; and/or (ii) COL1A2 FN1 SPP1 CTHRC1 POSTN MMP1in a biological sample from said individual wherein a higher level ofexpression of the genes or transcripts of group (i) and/or (ii) relativeto a gastrointestinal adenoma control level is indicative of a cancer ora cell predisposed to the onset of a cancerous state.

In yet another preferred embodiment the present invention is directed toa method of characterising a cell or cellular population, which cell orcellular population is derived from the large intestine of anindividual, said method comprising measuring the level of expression ofone or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i)200665_s_at 218468_s_at 211959_at 201744_s_at 202859_x_at; and/or (ii)SPARC GREM1 IGFBP5 LUM IL8in a biological sample from said individual wherein a higher level ofexpression of the genes or transcripts of group (i) and/or (ii) relativeto a gastrointestinal adenoma control level is indicative of a cancer ora cell predisposed to the onset of a cancerous state.

In still yet another preferred embodiment the present invention isdirected to a method of characterising a cell or cellular population,which cell or cellular population is derived from the large intestine ofan individual, said method comprising measuring the level of expressionof one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i)223122_s_at 207173_x_at 210511_s_at 212353_at 203083_at 209156_s_at219087_at 203477_at 224694_at 201438_at 37892_at 201141_at 226237_at202917_s_at 213905_x_at 225664_at 226930_at 205547_s_at 221730_at204051_s_at;_ and/or (ii) SFRP2 CDH11 INHBA SULF1 THBS2 COL6A2 ASPNCOL15A1 ANTXR1 COL6A3 COL11A1 GPNMB COL8A1 S100A8 BGN COL12A1 FNDC1TAGLN COL5A2 SFRP4in a biological sample from said individual wherein a higher level ofexpression of the genes or transcripts of group (i) and/or (ii) relativeto a gastrointestinal adenoma control level is indicative of a cancer ora cell predisposed to the onset of a cancerous state.

Preferably, said gastrointestinal tissue is colorectal tissue.

Even more preferably, said biological sample is a tissue sample.

In still another related aspect it has been determined that a subset ofthe markers of this aspect of the present invention are useful asqualitative markers of neoplastic tissue characterisation in that thesemarkers, if detectable above background levels in neoplastic tissue areindicative of either adenoma or cancerous tissue.

According to this aspect, the present invention provides a method ofcharacterising a neoplastic cell or cellular population, which cell orcellular population is derived from the large intestine of anindividual, said method comprising measuring the level of expression ofone or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i)235976_at 236894_at; and/or (ii) SLITRK6 L1TD1in a biological sample from said individual wherein a higher level ofexpression of the genes or transcripts of group (i) and/or (ii) relativeto neoplastic tissue background levels is indicative of an adenoma cellor a cell predisposed to the onset of an adenoma state.

In another aspect the present invention provides a method ofcharacterising a neoplastic cell or cellular population, which cell orcellular population is derived from the large intestine of anindividual, said method comprising measuring the level of expression ofone or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i)202311_s_at 209396_s_at 226237_at 204320_at 215646_s_at 227140_at204475_at 37892_at 229802_at 209395_at; and/or (ii) COL1A1 VCAN CHI3L1MMP1 COL8A1 COL11A1in a biological sample from said individual wherein a higher level ofexpression of the genes or transcripts of group (i) and/or (ii) relativeto neoplastic tissue background neoplastic cell levels is indicative ofa cancer or a cell predisposed to the onset of a cancerous state.

Preferably, said gastrointestinal tissue is colorectal tissue.

Still more preferably, said biological sample is a tissue sample.

In a most preferred embodiment, the methods of the present invention arepreferably directed to screening for proteins encoded by the markers ofthe present invention.

Although the preferred method is to detect the expression products ofthe neoplastic markers for the purpose of diagnosing neoplasiadevelopment or predisposition thereto, the detection of converse changesin the levels of said markers may be desired under certaincircumstances, for example, to monitor the effectiveness of therapeuticor prophylactic treatment directed to modulating a neoplastic condition,such as adenoma or adenocarcinoma development. For example, whereelevated levels of the subject markers indicate that an individual hasdeveloped a condition characterised by adenoma or adenocarcinomadevelopment, for example, screening for a decrease in the levels ofthese markers subsequently to the onset of a therapeutic regime may beutilised to indicate reversal or other form of improvement of thesubject individual's condition.

The method of the present invention is therefore useful as a one-timetest or as an on-going monitor of those individuals thought to be atrisk of neoplasia development or as a monitor of the effectiveness oftherapeutic or prophylactic treatment regimes directed to inhibiting orotherwise slowing neoplasia development. In these situations, mappingthe modulation of neoplastic marker expression levels in any one or moreclasses of biological samples is a valuable indicator of the status ofan individual or the effectiveness of a therapeutic or prophylacticregime which is currently in use. Accordingly, the method of the presentinvention should be understood to extend to monitoring for increases ordecreases in marker expression levels in an individual relative to theirnormal level (as hereinbefore defined), background control levels,cancer levels, adenoma levels or relative to one or more earlier markerexpression levels determined from a biological sample of saidindividual.

Means of testing for the subject expressed neoplasm markers in abiological sample can be achieved by any suitable method, which would bewell known to the person of skill in the art, such as but not limitedto:

(i) In vivo detection.

-   -   Molecular Imaging may be used following administration of        imaging probes or reagents capable of disclosing altered        expression of the markers in the intestinal tissues.    -   Molecular imaging (Moore et al., BBA, 1402:239-249, 1988;        Weissleder et al., Nature Medicine 6:351-355, 2000) is the in        vivo imaging of molecular expression that correlates with the        macro-features currently visualized using “classical” diagnostic        imaging techniques such as X-Ray, computed tomography (CT), MRI,        Positron Emission Tomography (PET) or endoscopy.

(ii) Detection of up-regulation of RNA expression in the cells byFluorescent In Situ Hybridization (FISH), or in extracts from the cellsby technologies such as Quantitative Reverse Transcriptase PolymeraseChain Reaction (QRTPCR) or Flow cytometric qualification of competitiveRT-PCR products (Wedemeyer et al., Clinical Chemistry 48:9 1398-1405,2002).

(iii) Assessment of expression profiles of RNA, for example by arraytechnologies (Alon et al., Proc. Natl. Acad. Sci. USA: 96, 6745-6750,June 1999).

-   -   A “microarray” is a linear or multi-dimensional array of        preferably discrete regions, each having a defined area, formed        on the surface of a solid support. The density of the discrete        regions on a microarray is determined by the total numbers of        target polynucleotides to be detected on the surface of a single        solid phase support. As used herein, a DNA microarray is an        array of oligonucleotide probes placed onto a chip or other        surfaces used to detect complementary oligonucleotides from a        complex nucleic acid mixture. Since the position of each        particular group of probes in the array is known, the identities        of the target polynucleotides can be determined based on their        binding to a particular position in the microarray.    -   Recent developments in DNA microarray technology make it        possible to conduct a large scale assay of a plurality of target        nucleic acid molecules on a single solid phase support. U.S.        Pat. No. 5,837,832 (Chee et al.) and related patent applications        describe immobilizing an array of oligonucleotide probes for        hybridization and detection of specific nucleic acid sequences        in a sample. Target polynucleotides of interest isolated from a        tissue of interest are hybridized to the DNA chip and the        specific sequences detected based on the target polynucleotides'        preference and degree of hybridization at discrete probe        locations. One important use of arrays is in the analysis of        differential gene expression, where the profile of expression of        genes in different cells or tissues, often a tissue of interest        and a control tissue, is compared and any differences in gene        expression among the respective tissues are identified. Such        information is useful for the identification of the types of        genes expressed in a particular tissue type and diagnosis of        conditions based on the expression profile.    -   In one example, RNA from the sample of interest is subjected to        reverse transcription to obtain labelled cDNA. See U.S. Pat. No.        6,410,229 (Lockhart et al.) The cDNA is then hybridized to        oligonucleotides or cDNAs of known sequence arrayed on a chip or        other surface in a known order. In another example, the RNA is        isolated from a biological sample and hybridised to a chip on        which are anchored cDNA probes. The location of the        oligonucleotide to which the labelled cDNA hybridizes provides        sequence information on the cDNA, while the amount of labelled        hybridized RNA or cDNA provides an estimate of the relative        representation of the RNA or cDNA of interest. See Schena, et        al. Science 270:467-470 (1995). For example, use of a cDNA        microarray to analyze gene expression patterns in human cancer        is described by DeRisi, et al. (Nature Genetics 14:457-460        (1996)).    -   In a preferred embodiment, nucleic acid probes corresponding to        the subject nucleic acids are made. The nucleic acid probes        attached to the microarray are designed to be substantially        complementary to the nucleic acids of the biological sample such        that specific hybridization of the target sequence and the        probes of the present invention occurs. This complementarity        need not be perfect, in that there may be any number of base        pair mismatches that will interfere with hybridization between        the target sequence and the single stranded nucleic acids of the        present invention. It is expected that the overall homology of        the genes at the nucleotide level probably will be about 40% or        greater, probably about 60% or greater, and even more probably        about 80% or greater; and in addition that there will be        corresponding contiguous sequences of about 8-12 nucleotides or        longer. However, if the number of mutations is so great that no        hybridization can occur under even the least stringent of        hybridization conditions, the sequence is not a complementary        target sequence. Thus, by “substantially complementary” herein        is meant that the probes are sufficiently complementary to the        target sequences to hybridize under normal reaction conditions,        particularly high stringency conditions.    -   A nucleic acid probe is generally single stranded but can be        partly single and partly double stranded. The strandedness of        the probe is dictated by the structure, composition, and        properties of the target sequence. In general, the        oligonucleotide probes range from about 6, 8, 10, 12, 15, 20, 30        to about 100 bases long, with from about 10 to about 80 bases        being preferred, and from about 15 to about 40 bases being        particularly preferred. That is, generally entire genes are        rarely used as probes. In some embodiments, much longer nucleic        acids can be used, up to hundreds of bases. The probes are        sufficiently specific to hybridize to a complementary template        sequence under conditions known by those of skill in the art.        The number of mismatches between the probe's sequences and their        complementary template (target) sequences to which they        hybridize during hybridization generally do not exceed 15%,        usually do not exceed 10% and preferably do not exceed 5%,        as-determined by BLAST (default settings).    -   Oligonucleotide probes can include the naturally-occurring        heterocyclic bases normally found in nucleic acids (uracil,        cytosine, thymine, adenine and guanine), as well as modified        bases and base analogues. Any modified base or base analogue        compatible with hybridization of the probe to a target sequence        is useful in the practice of the invention. The sugar or        glycoside portion of the probe can comprise deoxyribose, ribose,        and/or modified forms of these sugars, such as, for example,        2′-O-alkyl ribose. In a preferred embodiment, the sugar moiety        is 2′-deoxyribose; however, any sugar moiety that is compatible        with the ability of the probe to hybridize to a target sequence        can be used.    -   In one embodiment, the nucleoside units of the probe are linked        by a phosphodiester backbone, as is well known in the art. In        additional embodiments, internucleotide linkages can include any        linkage known to one of skill in the art that is compatible with        specific hybridization of the probe including, but not limited        to phosphorothioate, methylphosphonate, sulfamate (e.g., U.S.        Pat. No. 5,470,967) and polyamide (i.e., peptide nucleic acids).        Peptide nucleic acids are described in Nielsen et al. (1991)        Science 254: 1497-1500, U.S. Pat. No. 5,714,331, and        Nielsen (1999) Curr. Opin. Biotechnol. 10:71-75.    -   In certain embodiments, the probe can be a chimeric molecule;        i.e., can comprise more than one type of base or sugar subunit,        and/or the linkages can be of more than one type within the same        primer. The probe can comprise a moiety to facilitate        hybridization to its target sequence, as are known in the art,        for example, intercalators and/or minor groove binders.        Variations of the bases, sugars, and internucleoside backbone,        as well as the presence of any pendant group on the probe, will        be compatible with the ability of the probe to bind, in a        sequence-specific fashion, with its target sequence. A large        number of structural modifications, are possible within these        bounds. Advantageously, the probes according to the present        invention may have structural characteristics such that they        allow the signal amplification, such structural characteristics        being, for example, branched DNA probes as those described by        Urdea et al. (Nucleic Acids Symp. Ser., 24:197-200 (1991)) or in        the European Patent No. EP-0225,807. Moreover, synthetic methods        for preparing the various heterocyclic bases, sugars,        nucleosides and nucleotides that form the probe, and preparation        of oligonucleotides of specific predetermined sequence, are        well-developed and known in the art. A preferred method for        oligonucleotide synthesis incorporates the teaching of U.S. Pat.        No. 5,419,966.    -   Multiple probes may be designed for a particular target nucleic        acid to account for polymorphism and/or secondary structure in        the target nucleic acid, redundancy of data and the like. In        some embodiments, where more than one probe per sequence is        used, either overlapping probes or probes to different sections        of a single target gene are used. That is, two, three, four or        more probes, are used to build in a redundancy for a particular        target. The probes can be overlapping (i.e. have some sequence        in common), or are specific for distinct sequences of a gene.        When multiple target polynucleotides are to be detected        according to the present invention, each probe or probe group        corresponding to a particular target polynucleotide is situated        in a discrete area of the microarray.    -   Probes may be in solution, such as in wells or on the surface of        a micro-array, or attached to a solid support. Examples of solid        support materials that can be used include a plastic, a ceramic,        a metal, a resin, a gel and a membrane. Useful types of solid        supports include plates, beads, magnetic material, microbeads,        hybridization chips, membranes, crystals, ceramics and        self-assembling monolayers. One example comprises a        two-dimensional or three-dimensional matrix, such as a gel or        hybridization chip with multiple probe binding sites (Pevzner et        al., J. Biomol. Struc. & Dyn. 9:399-410, 1991; Maskos and        Southern, Nuc. Acids Res. 20:1679-84, 1992). Hybridization chips        can be used to construct very large probe arrays that are        subsequently hybridized with a target nucleic acid. Analysis of        the hybridization pattern of the chip can assist in the        identification of the target nucleotide sequence. Patterns can        be manually or computer analyzed, but it is clear that        positional sequencing by hybridization lends itself to computer        analysis and automation. In another example, one may use an        Affymetrix chip on a solid phase structural support in        combination with a fluorescent bead based approach. In yet        another example, one may utilise a cDNA microarray. In this        regard, the oligonucleotides described by Lockkart et al. (i.e.        Affymetrix synthesis probes in situ on the solid phase) are        particularly preferred, that is, photolithography.    -   As will be appreciated by those in the art, nucleic acids can be        attached or immobilized to a solid support in a wide variety of        ways. By “immobilized” herein is meant the association or        binding between the nucleic acid probe and the solid support is        sufficient to be stable under the conditions of binding,        washing, analysis, and removal. The binding can be covalent or        non-covalent. By “non-covalent binding” and grammatical        equivalents herein is meant one or more of either electrostatic,        hydrophilic, and hydrophobic interactions. Included in        non-covalent binding is the covalent attachment of a molecule,        such as streptavidin, to the support and the non-covalent        binding of the biotinylated probe to the streptavidin. By        “covalent binding” and grammatical equivalents herein is meant        that the two moieties, the solid support and the probe, are        attached by at least one bond, including sigma bonds, pi bonds        and coordination bonds. Covalent bonds can be formed directly        between the probe and the solid support or can be formed by a        cross linker or by inclusion of a specific reactive group on        either the solid support or the probe or both molecules.        Immobilization may also involve a combination of covalent and        non-covalent interactions.    -   Nucleic acid probes may be attached to the solid support by        covalent binding such as by conjugation with a coupling agent or        by covalent or non-covalent binding such as electrostatic        interactions, hydrogen bonds or antibody-antigen coupling, or by        combinations thereof. Typical coupling agents include        biotin/avidin, biotin/streptavidin, Staphylococcus aureus        protein A/IgG antibody F_(c) fragment, and streptavidin/protein        A chimeras (T. Sano and C. R. Cantor, Bio/Technology 9:1378-81        (1991)), or derivatives or combinations of these agents. Nucleic        acids may be attached to the solid support by a photocleavable        bond, an electrostatic bond, a disulfide bond, a peptide bond, a        diester bond or a combination of these sorts of bonds. The array        may also be attached to the solid support by a selectively        releasable bond such as 4,4′-dimethoxytrityl or its derivative.        Derivatives which have been found to be useful include 3 or 4        [bis-(4-methoxyphenyl)]-methyl-benzoic acid, N-succinimidyl-3 or        4 [bis-(4-methoxyphenyl)]-methyl-benzoic acid, N-succinimidyl-3        or 4 [bis-(4-methoxyphenyl)]-hydroxymethyl-benzoic acid,        N-succinimidyl-3 or 4        [bis-(4-methoxyphenyl)]-chloromethyl-benzoic acid, and salts of        these acids.    -   In general, the probes are attached to the microarray in a wide        variety of ways, as will be appreciated by those in the art. As        described herein, the nucleic acids can either be synthesized        first, with subsequent attachment to the microarray, or can be        directly synthesized on the microarray.    -   The microarray comprises a suitable solid substrate. By        “substrate” or “solid support” or other grammatical equivalents        herein is meant any material that can be modified to contain        discrete individual sites appropriate for the attachment or        association of the nucleic acid probes and is amenable to at        least one detection method. The solid phase support of the        present invention can be of any solid materials and structures        suitable for supporting nucleotide hybridization and synthesis.        Preferably, the solid phase support comprises at least one        substantially rigid surface on which the primers can be        immobilized and the reverse transcriptase reaction performed.        The substrates with which the polynucleotide microarray elements        are stably associated and may be fabricated from a variety of        materials, including plastics, ceramics, metals, acrylamide,        cellulose, nitrocellulose, glass, polystyrene, polyethylene        vinyl acetate, polypropylene, polymethacrylate, polyethylene,        polyethylene oxide, polysilicates, polycarbonates, Teflon,        fluorocarbons, nylon, silicon rubber, polyanhydrides,        polyglycolic acid, polylactic acid, polyorthoesters,        polypropylfumerate, collagen, glycosaminoglycans, and polyamino        acids. Substrates may be two-dimensional or three-dimensional in        form, such as gels, membranes, thin films, glasses, plates,        cylinders, beads, magnetic beads, optical fibers, woven fibers,        etc. A preferred form of array is a three-dimensional array. A        preferred three-dimensional array is a collection of tagged        beads. Each tagged bead has different primers attached to it.        Tags are detectable by signalling means such as color (Luminex,        Illumina) and electromagnetic field (Pharmaseq) and signals on        tagged beads can even be remotely detected (e.g., using optical        fibers). The size of the solid support can be any of the        standard microarray sizes, useful for DNA microarray technology,        and the size may be tailored to fit the particular machine being        used to conduct a reaction of the invention. In general, the        substrates allow optical detection and do not appreciably        fluoresce.    -   In one embodiment, the surface of the microarray and the probe        may be derivatized with chemical functional groups for        subsequent attachment of the two. Thus, for example, the        microarray is derivatized with a chemical functional group        including, but not limited to, amino groups, carboxy groups, oxo        groups and thiol groups, with amino groups being particularly        preferred. Using these functional groups, the probes can be        attached using functional groups on the probes. For example,        nucleic acids containing amino groups can be attached to        surfaces comprising amino groups, for example using linkers as        are known in the art; for example, homo-or hetero-bifunctional        linkers as are well known. In addition, in some cases,        additional linkers, such as alkyl groups (including substituted        and heteroalkyl groups) may be used.    -   In this embodiment, the oligonucleotides are synthesized as is        known in the art, and then attached to the surface of the solid        support. As will be appreciated by those skilled in the art,        either the 5′ or 3′ terminus may be attached to the solid        support, or attachment may be via an internal nucleoside. In an        additional embodiment, the immobilization to the solid support        may be very strong, yet non-covalent. For example, biotinylated        oligonucleotides can be made, which bind to surfaces covalently        coated with streptavidin, resulting in attachment.    -   The arrays may be produced according to any convenient        methodology, such as preforming the polynucleotide microarray        elements and then stably associating them with the surface.        Alternatively, the oligonucleotides may be synthesized on the        surface, as is known in the art. A number of different array        configurations and methods for their production are known to        those of skill in the art and disclosed in WO 95/25116 and WO        95/35505 (photolithographic techniques), U.S. Pat. No. 5,445,934        (in situ synthesis by photolithography), U.S. Pat. No. 5,384,261        (in situ synthesis by mechanically directed flow paths); and        U.S. Pat. No. 5,700,637 (synthesis by spotting, printing or        coupling); the disclosure of which are herein incorporated in        their entirety by reference. Another method for coupling DNA to        beads uses specific ligands attached to the end of the DNA to        link to ligand-binding molecules attached to a bead. Possible        ligand-binding partner pairs include biotin-avidin/streptavidin,        or various antibody/antigen pairs such as        digoxygenin-antidigoxygenin antibody (Smith et al., Science        258:1122-1126 (1992)). Covalent chemical attachment of DNA to        the support can be accomplished by using standard coupling        agents to link the 5′-phosphate on the DNA to coated        microspheres through a phosphoamidate bond. Methods for        immobilization of oligonucleotides to solid-state substrates are        well established. See Pease et al., Proc. Natl. Acad. Sci. USA        91(11):5022-5026 (1994). A preferred method of attaching        oligonucleotides to solid-state substrates is described by Guo        et al., Nucleic Acids Res. 22:5456-5465 (1994). Immobilization        can be accomplished either by in situ DNA synthesis (Maskos and        Southern, supra) or by covalent attachment of chemically        synthesized oligonucleotides (Guo et al., supra) in combination        with robotic arraying technologies.    -   In addition to the solid-phase technology represented by        microarray arrays, gene expression can also be quantified using        liquid-phase assays. One such system is kinetic polymerase chain        reaction (PCR). Kinetic PCR allows for the simultaneous        amplification and quantification of specific nucleic acid        sequences. The specificity is derived from synthetic        oligonucleotide primers designed to preferentially adhere to        single-stranded nucleic acid sequences bracketing the target        site. This pair of oligonucleotide primers form specific,        non-covalently bound complexes on each strand of the target        sequence. These complexes facilitate in vitro transcription of        double-stranded DNA in opposite orientations. Temperature        cycling of the reaction mixture creates a continuous cycle of        primer binding, transcription, and re-melting of the nucleic        acid to individual strands. The result is an exponential        increase of the target dsDNA product. This product can be        quantified in real time either through the use of an        intercalating dye or a sequence specific probe. SYBR(r) Green 1,        is an example of an intercalating dye, that preferentially binds        to dsDNA resulting in a concomitant increase in the fluorescent        signal. Sequence specific probes, such as used with TaqMan        technology, consist of a fluorochrome and a quenching molecule        covalently bound to opposite ends of an oligonucleotide. The        probe is designed to selectively bind the target DNA sequence        between the two primers. When the DNA strands are synthesized        during the PCR reaction, the fluorochrome is cleaved from the        probe by the exonuclease activity of the polymerase resulting in        signal dequenching. The probe signalling method can be more        specific than the intercalating dye method, but in each case,        signal strength is proportional to the dsDNA product produced.        Each type of quantification method can be used in multi-well        liquid phase arrays with each well representing primers and/or        probes specific to nucleic acid sequences of interest. When used        with messenger RNA preparations of tissues or cell lines, an        array of probe/primer reactions can simultaneously quantify the        expression of multiple gene products of interest. See Germer et        al., Genome Res. 10:258-266 (2000); Heid et al., Genome Res.        6:986-994 (1996).

(iv) Measurement of altered neoplastic marker protein levels in cellextracts, for example by immunoassay.

-   -   Testing for proteinaceous neoplastic marker expression product        in a biological sample can be performed by any one of a number        of suitable methods which are well known to those skilled in the        art. Examples of suitable methods include, but are not limited        to, antibody screening of tissue sections, biopsy specimens or        bodily fluid samples.    -   To the extent that antibody based methods of diagnosis are used,        the presence of the marker protein may be determined in a number        of ways such as by Western blotting, ELISA or flow cytometry        procedures. These, of course, include both single-site and        two-site or “sandwich” assays of the non-competitive types, as        well as in the traditional competitive binding assays. These        assays also include direct binding of a labelled antibody to a        target.    -   Sandwich assays are among the most useful and commonly used        assays. A number of variations of the sandwich assay technique        exist, and all are intended to be encompassed by the present        invention. Briefly, in a typical forward assay, an unlabelled        antibody is immobilized on a solid substrate and the sample to        be tested brought into contact with the bound molecule. After a        suitable period of incubation, for a period of time sufficient        to allow formation of an antibody-antigen complex, a second        antibody specific to the antigen, labelled with a reporter        molecule capable of producing a detectable signal is then added        and incubated, allowing time sufficient for the formation of        another complex of antibody-antigen-labelled antibody. Any        unreacted material is washed away, and the presence of the        antigen is determined by observation of a signal produced by the        reporter molecule. The results may either be qualitative, by        simple observation of the visible signal, or may be quantitated        by comparing with a control sample. Variations on the forward        assay include a simultaneous assay, in which both sample and        labelled antibody are added simultaneously to the bound        antibody. These techniques are well known to those skilled in        the art, including any minor variations as will be readily        apparent.    -   In the typical forward sandwich assay, a first antibody having        specificity for the marker or antigenic parts thereof, is either        covalently or passively bound to a solid surface. The solid        surface is typically glass or a polymer, the most commonly used        polymers being cellulose, polyacrylamide, nylon, polystyrene,        polyvinyl chloride or polypropylene. The solid supports may be        in the form of tubes, beads, discs of microplates, or any other        surface suitable for conducting an immunoassay. The binding        processes are well-known in the art and generally consist of        cross-linking, covalently binding or physically adsorbing, the        polymer-antibody complex is washed in preparation for the test        sample. An aliquot of the sample to be tested is then added to        the solid phase complex and incubated for a period of time        sufficient (e.g. 2-40 minutes) and under suitable conditions        (e.g. 25° C.) to allow binding of any subunit present in the        antibody. Following the incubation period, the antibody subunit        solid phase is washed and dried and incubated with a second        antibody specific for a portion of the antigen. The second        antibody is linked to a reporter molecule which is used to        indicate the binding of the second antibody to the antigen.    -   An alternative method involves immobilizing the target molecules        in the biological sample and then exposing the immobilized        target to specific antibody which may or may not be labelled        with a reporter molecule. Depending on the amount of target and        the strength of the reporter molecule signal, a bound target may        be detectable by direct labelling with the antibody.        Alternatively, a second labelled antibody, specific to the first        antibody is exposed to the target-first antibody complex to form        a target-first antibody-second antibody tertiary complex. The        complex is detected by the signal emitted by the reporter        molecule.    -   By “reporter molecule” as used in the present specification, is        meant a molecule which, by its chemical nature, provides an        analytically identifiable signal which allows the detection of        antigen-bound antibody. Detection may be either qualitative or        quantitative. The most commonly used reporter molecules in this        type of assay are either enzymes, fluorophores or radionuclide        containing molecules (i.e. radioisotopes) and chemiluminescent        molecules.    -   In the case of an enzyme immunoassay, an enzyme is conjugated to        the second antibody, generally by means of glutaraldehyde or        periodate. As will be readily recognized, however, a wide        variety of different conjugation techniques exist, which are        readily available to the skilled artisan. Commonly used enzymes        include horseradish peroxidase, glucose oxidase,        beta-galactosidase and alkaline phosphatase, amongst others. The        substrates to be used with the specific enzymes are generally        chosen for the production, upon hydrolysis by the corresponding        enzyme, of a detectable color change. Examples of suitable        enzymes include alkaline phosphatase and peroxidase. It is also        possible to employ fluorogenic substrates, which yield a        fluorescent product rather than the chromogenic substrates noted        above. In all cases, the enzyme-labelled antibody is added to        the first antibody hapten complex, allowed to bind, and then the        excess reagent is washed away. A solution containing the        appropriate substrate is then added to the complex of        antibody-antigen-antibody. The substrate will react with the        enzyme linked to the second antibody, giving a qualitative        visual signal, which may be further quantitated, usually        spectrophotometrically, to give an indication of the amount of        antigen which was present in the sample. “Reporter molecule”        also extends to use of cell agglutination or inhibition of        agglutination such as red blood cells on latex beads, and the        like.    -   Alternately, fluorescent compounds, such as fluorecein and        rhodamine, may be chemically coupled to antibodies without        altering their binding capacity. When activated by illumination        with light of a particular wavelength, the fluorochrome-labelled        antibody adsorbs the light energy, inducing a state to        excitability in the molecule, followed by emission of the light        at a characteristic color visually detectable with a light        microscope. As in the EIA, the fluorescent labelled antibody is        allowed to bind to the first antibody-hapten complex. After        washing off the unbound reagent, the remaining tertiary complex        is then exposed to the light of the appropriate wavelength the        fluorescence observed indicates the presence of the hapten of        interest. Immunofluorescence and EIA techniques are both very        well established in the art and are particularly preferred for        the present method. However, other reporter molecules, such as        radioisotope, chemiluminescent or bioluminescent molecules, may        also be employed.

(v) Without limiting the present invention to any one theory or mode ofaction, during development gene expression is regulated by processesthat alter the availability of genes for expression in different celllineages without any alteration in gene sequence, and these states canbe inherited through a cell division—a process called epigeneticinheritance. Epigenetic inheritance is determined by a combination ofDNA methylation (modification of cytosine to give 5-methyl cytosine,5meC) and by modifications of the histone chromosomal proteins thatpackage DNA. Thus methylation of DNA at CpG sites and modifications suchas deacetylation of histone H3 on lysine 9, and methylation on lysine 9or 27 are associated with inactive chromatin, while the converse stateof a lack of DNA methylation, acetylation of lysine 9 of histone H3 isassociated with open chromatin and active gene expression. In cancer,this epigenetic regulation of gene expression is frequently found to bedisrupted (Esteller & Herman, 2000; Jones & Baylin, 2002). Genes such astumour suppressor or metastasis suppressor genes are often found to besilenced by DNA methylation, while other genes may be hypomethylated andinappropriately expressed. Thus, among genes that elevated orinappropriate expression in cancer, this in some instances ischaracterised by a loss of methylation of the promoter or regulatoryregion of the gene.

-   -   A variety of methods are available for detection of aberrantly        methylated DNA of a specific gene, even in the presence of a        large excess of normal DNA (Clark 2007). Thus, elevated        expression of certain genes may be detected through detection of        the presence of hypomethylated sequences in tissue, bodily fluid        or other patient samples.    -   Epigenetic alterations and chromatin changes in cancer are also        evident in the altered association of modified histones with        specific genes(Esteller, 2007); for example activated genes are        often found associated with histone H3 that is acetylated on        lysine 9 and methylated on lysine 4. The use of antibodies        targeted to altered histones allows for the isolation of DNA        associated with particular chromatin states and has potential        use in cancer diagnosis.

(vi) Determining altered expression of protein neoplastic markers on thecell surface, for example by immunohistochemistry.

(vii) Determining altered protein expression based on any suitablefunctional test, enzymatic test or immunological test in addition tothose detailed in points (iv) and (v) above.

A person of ordinary skill in the art could determine, as a matter ofroutine procedure, the appropriateness of applying a given method to aparticular type of biological sample.

Without limiting the present invention in any way, and as detailedabove, gene expression levels can be measured by a variety of methodsknown in the art. For example, gene transcription or translationproducts can be measured. Gene transcription products, i.e., RNA, can bemeasured, for example, by hybridization assays, run-off assays, Northernblots, or other methods known in the art.

Hybridization assays generally involve the use of oligonucleotide probesthat hybridize to the single-stranded RNA transcription products. Thus,the oligonucleotide probes are complementary to the transcribed RNAexpression product. Typically, a sequence-specific probe can be directedto hybridize to RNA or cDNA. A “nucleic acid probe”, as used herein, canbe a DNA probe or an RNA probe that hybridizes to a complementarysequence. One of skill in the art would know how to design such a probesuch that sequence specific hybridization will occur. One of skill inthe art will further know how to quantify the amount of sequencespecific hybridization as a measure of the amount of gene expression forthe gene was transcribed to produce the specific RNA.

The hybridization sample is maintained under conditions that aresufficient to allow specific hybridization of the nucleic acid probe toa specific gene expression product. “Specific hybridization”, as usedherein, indicates near exact hybridization (e.g., with few if anymismatches). Specific hybridization can be performed under highstringency conditions or moderate stringency conditions. In oneembodiment, the hybridization conditions for specific hybridization arehigh stringency. For example, certain high stringency conditions can beused to distinguish perfectly complementary nucleic acids from those ofless complementarity. “High stringency conditions”, “moderate stringencyconditions” and “low stringency conditions” for nucleic acidhybridizations are explained on pages 2.10.1-2.10.16 and pages6.3.1-6.3.6 in Current Protocols in Molecular Biology (Ausubel, F. etal., “Current Protocols in Molecular Biology”, John Wiley & Sons,(1998), the entire teachings of which are incorporated by referenceherein). The exact conditions that determine the stringency ofhybridization depend not only on ionic strength (e.g., 0.2.times.SSC,0.1.times.SSC), temperature (e.g., room temperature, 42° C., 68° C.) andthe concentration of destabilizing agents such as formamide ordenaturing agents such as SDS, but also on factors such as the length ofthe nucleic acid sequence, base composition, percent mismatch betweenhybridizing sequences and the frequency of occurrence of subsets of thatsequence within other non-identical sequences. Thus, equivalentconditions can be determined by varying one or more of these parameterswhile maintaining a similar degree of identity or similarity between thetwo nucleic acid molecules. Typically, conditions are used such thatsequences at least about 60%, at least about 70%, at least about 80%, atleast about 90% or at least about 95% or more identical to each otherremain hybridized to one another. By varying hybridization conditionsfrom a level of stringency at which no hybridization occurs to a levelat which hybridization is first observed, conditions that will allow agiven sequence to hybridize (e.g., selectively) with the mostcomplementary sequences in the sample can be determined.

Exemplary conditions that describe the determination of wash conditionsfor moderate or low stringency conditions are described in Kraus, M. andAaronson, S., 1991. Methods Enzymol., 200:546-556; and in, Ausubel etal., Current Protocols in Molecular Biology, John Wiley & Sons, (1998).Washing is the step in which conditions are usually set so as todetermine a minimum level of complementarity of the hybrids. Generally,starting from the lowest temperature at which only homologoushybridization occurs, each ° C. by which the final wash temperature isreduced (holding SSC concentration constant) allows an increase by 1% inthe maximum mismatch percentage among the sequences that hybridize.Generally, doubling the concentration of SSC results in an increase inT_(m) of about 17° C. Using these guidelines, the wash temperature canbe determined empirically for high, moderate or low stringency,depending on the level of mismatch sought. For example, a low stringencywash can comprise washing in a solution containing 0.2.times.SSC/0.1%SDS for 10 minutes at room temperature; a moderate stringency wash cancomprise washing in a pre-warmed solution (42° C.) solution containing0.2.times.SSC/0.1% SDS for 15 minutes at 42° C.; and a high stringencywash can comprise washing in pre-warmed (68° C.) solution containing0.1.times.SSC/0.1% SDS for 15 minutes at 68° C. Furthermore, washes canbe performed repeatedly or sequentially to obtain a desired result asknown in the art. Equivalent conditions can be determined by varying oneor more of the parameters given as an example, as known in the art,while maintaining a similar degree of complementarity between the targetnucleic acid molecule and the primer or probe used (e.g., the sequenceto be hybridized).

A related aspect of the present invention provides a molecular array,which array comprises a plurality of:

-   -   (i) nucleic acid molecules comprising a nucleotide sequence        corresponding to any one or more of the neoplastic marker genes        hereinbefore described or a sequence exhibiting at least 80%        identity thereto or a functional derivative, fragment, variant        or homologue of said nucleic acid molecule; or    -   (ii) nucleic acid molecules comprising a nucleotide sequence        capable of hybridising to any one or more of the sequences        of (i) under medium stringency conditions or a functional        derivative, fragment, variant or homologue of said nucleic acid        molecule; or    -   (iii) nucleic acid probes or oligonucleotides comprising a        nucleotide sequence capable of hybridising to any one or more of        the sequences of (i) under medium stringency conditions or a        functional derivative, fragment, variant or homologue of said        nucleic acid molecule; or    -   (iv) probes capable of binding to any one or more of the        proteins encoded by the nucleic acid molecules of (i) or a        derivative, fragment or, homologue thereof        wherein the level of expression of said marker genes of (i) or        proteins of (iv) is indicative of the neoplastic state of a cell        or cellular subpopulation derived from the large intestine.

Preferably, said percent identity is at least 85%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98% or 99%.

Low stringency includes and encompasses from at least about 1% v/v to atleast about 15% v/v formamide and from at least about 1M to at leastabout 2M salt for hybridisation, and at least about 1M to at least about2M salt for washing conditions. Alternative stringency conditions may beapplied where necessary, such as medium stringency, which includes andencompasses from at least about 16% v/v at least about 30% v/v formamideand from at least about 0.5M to at least about 0.9M salt forhybridisation, and at least about 0.5M to at least about 0.9M salt forwashing conditions, or high stringency, which includes and encompassesfrom at least about 31% v/v to at least about 50% v/v formamide and fromat least about 0.01M to at least about 0.15M salt for hybridisation, andat least about 0.01M to at least about 0.15M salt for washingconditions. In general, washing is carried out at T_(m)=69.3 +0.41 (G+C)% [19]=−12° C. However, the T_(m) of a duplex DNA decreases by 1° C.with every increase of 1% in the number of mismatched based pairs(Bonner et al (1973) J. Mol. Biol. 81:123).

Preferably, the subject probes are designed to bind to the nucleic acidor protein to which they are directed with a level of specificity whichminimises the incidence of non-specific reactivity. However, it would beappreciated that it may not be possible to eliminate all potentialcross-reactivity or non-specific reactivity, this being an inherentlimitation of any probe based system.

In terms of the probes which are used to detect the subject proteins,they may take any suitable form including antibodies and aptamers.

A library or array of nucleic acid or protein probes provides rich andhighly valuable information. Further, two or more arrays or profiles(information obtained from use of an array) of such sequences are usefultools for comparing a test set of results with a reference, such asanother sample or stored calibrator. In using an array, individualprobes typically are immobilized at separate locations and allowed toreact for binding reactions. Primers associated with assembled sets ofmarkers are useful for either preparing libraries of sequences ordirectly detecting markers from other biological samples.

A library (or array, when referring to physically separated nucleicacids corresponding to at least some sequences in a library) of genemarkers exhibits highly desirable properties. These properties areassociated with specific conditions, and may be characterized asregulatory profiles. A profile, as termed here refers to a set ofmembers that provides diagnostic information of the tissue from whichthe markers were originally derived. A profile in many instancescomprises a series of spots on an array made from deposited sequences.

A characteristic patient profile is generally prepared by use of anarray. An array profile may be compared with one or more other arrayprofiles or other reference profiles. The comparative results canprovide rich information pertaining to disease states, developmentalstate, receptiveness to therapy and other information about the patient.

Another aspect of the present invention provides a diagnostic kit forassaying biological samples comprising an agent for detecting one ormore neoplastic markers and reagents useful for facilitating thedetection by said agent. Further means may also be included, forexample, to receive a biological sample. The agent may be any suitabledetecting molecule.

The present invention is further described by the following non-limitingexamples:

EXAMPLE 1

Methods and Materials

Affymetrix GeneChip Data

Gene expression profiling data and accompanying clinical data waspurchased from GeneLogic Inc (Gaithersburg, Md. USA). For each tissueanalyzed, oligonucleotide microarray data for 44,928 probesets(Affymetrix HGU133A & HGU133B, combined), experimental and clinicaldescriptors, and digitally archived microscopy images of histologicalpreparations were received. A quality control analysis was performed toremove arrays not meeting essential quality control measures as definedby the manufacturer.

Transcript expression levels were calculated by both Microarray Suite(MAS) 5.0 (Affymetrix) and the Robust Multichip Average (RMA)normalization techniques (Affymetrix. GeneChip expression data analysisfundamentals. Affymetrix, Santa Clara, Calif. USA, 2001; Hubbell et al.Bioinformatics, 18:1585-1592, 2002; Irizarry et al. Nucleic AcidResearch, 31, 2003)MAS normalized data was used for performing standardquality control routines and the final data set was normalized with RMAfor all subsequent analyses.

Univariate Differential Expression

Differentially expressed gene transcripts were identified using amoderated t-test implemented in the limma library downloaded from theBioconductor repository for R. (G. K. Smyth. Statistical Applications inGenetics and Molecular Biology, 3(1):Article 3, 2004; G K Smyth.Bioinformatics and Computational Biology Solutions using R andBioconductor. Springer, N.Y., 2005). Significance estimates (p-values)were corrected to adjust for multiple hypothesis testing using theBonferonni correction.

Tissue Specific Expression Patterns

To construct a filter for hypothetically ‘turned on’ gene expression themean expression level for all 44,928 probesets across the full range of454 tissues was first estimated. To estimate an expression on/offthreshold, the 44,928 mean values were ranked and the expression valueequivalent to the 30th percentile across the dataset calculated. Thisarbitrary threshold was chosen because it was theorized that themajority of transcripts (and presumably more than 30%) in a givenspecimen should be transcriptionally silenced. Thus this thresholdrepresents a conservative upper bound for what is estimated asnon-specific, or background, signal.

Gene Symbol Annotations

To map Affymetrix probeset names to official gene symbols the annotationmetadata available from Bioconductor was used. hgu133plus2 libraryversion 1.16.0, which was assembled using Entrez Gene data downloaded on15 Mar. 2007, was used.

Estimates of Performance Characteristics

Diagnostic utility for each table of markers shown herein was estimatedincluding: sensitivity, specificity, positive predictive value, negativepredictive value, likelihood ratio positive, likelihood ratio negative.These estimates were calculated in the same data used to discover themarkers and will therefore potentially overestimate the performancecharacteristics in future tissue samples. To improve the generalisabiltyof the estimates a modified jackknife resampling technique was used tocalculate a less biased value for each characteristic.

Results

A range of univariate statistical tests were applied on Affymetrixoligonucleotide microarray data to reveal human genes that could be usedto discriminate colorectal neoplastic tissues from non-neoplastictissues. There were further identified a number of gene transcripts thatappear to be useful for differentiating colorectal adenomas fromcolorectal carcinoma. Also identified were a subset of these transcriptsthat may have particular diagnostic utility because due to the proteinproducts being either secreted or displayed on the cell surface ofepithelial cells. Finally, there were identified a further subset oftranscripts expressed specifically in neoplastic tissues and at low- ornear-background levels in non-neoplastic tissues.

Genes Differentially Expressed in Neoplastic Tissues

From a total GeneChip set of 44,928 probesets it was determined thatover 11,000 probesets were differentially expressed by moderated t-testusing the limma package in BioConductor (G. K. Smyth, 2004 supra)employing conservative (Bonferroni) multiple test correction. When thislist was further filtered to include only those probesets demonstratinga 2-fold or greater mean expression change between the neoplastic andnon-neoplastic tissues, 206 probesets were found to be expressed higherin neoplasias relative to normals.

These 205 probesets were annotated using the most recent metadata andannotation packages available for the chips. The 205 overexpressedprobesets were mapped to 174 gene symbols.

Δ-expression ProbeSet ID Gene Symbol Maps UP 205 157

Hypothetical Markers Specific for Colorectal Neoplasia

While differential gene expression patterns are useful for diagnosticpurposes, this project also seeks to identify diagnostic proteins shedinto the lumen of the gut by neoplastic colorectal epithelia. Todiscover candidate proteins the list of differentially expressedtranscripts were filtered with a selection criteria aimed at identifyingmarkers specifically expressed in colorectal neoplasia tissues. Thisfilter criteria is based on a theoretical assumption that most genes onthe GeneChip will be turned ‘off’ and that any microarray signals forsuch ‘off’ transcripts will reflect technical assay background andnon-specific oligonucleotide binding. Accordingly, to select genesspecifically expressed in neoplastic tumours (i.e. ‘on’) thenon-neoplastic signals were compared with a hypothetical backgroundsignal threshold from across all genes on the chip. By design, alltranscripts in the candidate pool from which the ‘on’ transcripts arechosen are at least two fold overexpressed in the diseased tissues.Combined, it is hypothesized that these criteria yield the subset ofdifferentially expressed genes that are specifically expressed inneoplasia. The expression profile for a representative ‘on’ transcriptis shown in FIG. 1.

Genes Differentially Expressed Between Adenomas and Cancer Tissues

There were 33 transcripts observed that were differentially expressed atleast two-fold higher in adenoma tissues relative to cancer tissues. Inparticular, there were identified several transcripts that exhibit anexpression pattern specific for adenomas, including SLITRK6 and L1TD1,shown in FIG. 2.

Further, there were also identified cancer specific transcripts. Theexpression profile of one such transcript, COL11A1 is shown in FIG. 3.

EXAMPLE 2 Probesets Elevated in Neoplasia

Differential expression analysis was applied to Affymetrix gene chipdata measuring RNA concentration in 454 colorectal tissues including 161adenocarcinoma specimens, 29 adenoma specimens, 42 colitis specimens and222 non-diseased tissues. Using conservative corrections for multiplehypothesis testing, it was determined that over 25% of the 44,928probesets measured in each tissue experiment were differentiallyexpressed between the 190 neoplasia specimens and 264 non-neoplasiacontrols. To identify robust biomarkers for colorectal neoplasia thelist of putative probeset biomarkers were further filtered to includeonly those probesets shown to be expressed at least 2-fold higher inneoplastic vs. non-neoplastic tissues.

205 probesets hybridising to approximately 157 putative genes wereobserved to be expressed at a statistically significant higher level inneoplastic tissues relative to non-neoplastic controls.

Validation/Hypothesis Testing

To validate these discovery results the hybridisation of 199 candidateprobesets were measured against RNA extracts from 68 clinical specimenscomprising 19 adenomas, 19 adenocarcinomas, and 30 non-diseased controlsusing a custom-designed ‘Adenoma Gene Chip’. Six (6) probesets were nottested as they were not included on the custom design. It was confirmedthat 186/199 (88%) of the target probesets or probesets which alsohybridise to the target locus were likewise differentially expressed(P<0.05) in these independently-derived tissues. The results of testingthese probesets in 68 independently collected clinical specimens isshown in Table 1.

We further tested the 142 of the 157 unique gene loci to which the 205probesets are understood to hybridise. We note the remaining 15 genesymbols were not represented in the validation data. We observed that133 of 142 gene symbols were represented in the validation data by atleast one differentially expressed probeset and many symbols includedmultiple probesets against regions across the putative locus. A completelist of probesets that bind to target loci is shown in Table 2.

Conclusion

The candidate probesets shown in Tables 1 and 2 are differentiallyexpressed in neoplastic colorectal tissues compared to non-neoplasticcontrols.

EXAMPLE 3 Probesets Demonstrating a Neoplasia-Specific Profile

During analysis of the data, a novel expression profile was observedbetween neoplastic and non-neoplastic phenotypes. It was hypothesizedthat a subset of quantitatively differentially expressed probesets arefurthermore qualitatively differentially expressed. Such probesets showevidence of a neoplasia-specific gene expression profile, i.e. theseprobesets appear to be expressed above background levels in neoplastictissues only. This observation and the resulting hypothesis are based ontwo principles:

-   -   1. That the majority of human transcripts that are present on a        genome-wide GeneChip (e.g. U133) will not likely be expressed in        the colorectal mucosa; and    -   2. That microarray binding intensity for such ‘off’ probesets to        labelled cRNA will reflect technical assay background, i.e.        non-specific oligonucleotide binding.

To generate a list of neoplasia specific probesets the non-neoplasticintensity of differentially expressed probesets was compared with ahypothetical background signal threshold from across all probesets onthe chip. Bydesign, all probesets in the candidate pool from which the‘on’ transcripts are chosen are at least two fold over-expressed in thediseased tissues. Combined, these criteria yield the subset ofdifferentially expressed transcript species that are specificallyexpressed in neoplasia.

Validation/Hypothesis Testing

The custom gene chip design precludes testing the hypotheticallyneoplasia-specific probesets using the same principles as used fordiscovery. In particular, the custom gene chip (by design) does notcontain a large pool of probesets anticipated to hybridise tohypothetically ‘off’/'non-transcribed' gene transcripts. This is becausethe custom gene chip design is biased toward differentially expressedtranscripts in colorectal neoplastic tissues.

The usual differential expression testing (limma) was therefore to thesecandidate probesets for neoplasia-specific transcripts. Of the 33probesets on the custom gene chip, 32 probesets (or probesets which bindto the same locus) were differentially expressed between the 38neoplastic tissues (adenoma & cancer) and non-neoplastic controls. Theresults of these validation experiments is shown in Table 3.

All probesets which are known to hybridise to the gene loci to which the33 probesets claimed herein were tested. Of the 32 putative gene locitargeted by the probesets, 29 were present in the validation data.Twenty-eight (28) of these 29 gene symbols demonstrated at least onehybridising probeset which was differentially expressed in theneoplastic tissues. Results for these experiments, including allprobesets that bind to each target locus in a differentially expressedmanner are shown in Table 4.

EXAMPLE 4 Probesets Useful for Characterizing Neoplastic Tissues

Differential expression analysis was applied to Affymetrix gene chipdata measuring RNA concentration in neoplastic tissues including 161adenocarcinoma specimens and 29 adenoma specimens. It was observed that43 probesets hybridizing to approximately 33 putative gene symbols wereexpressed higher (P<0.05) in adenoma tissues relative to cancer tissues.Conversely, 145 probesets (104 gene symbols) were identified to beexpressed higher in cancer relative to adenomas.

Validation/Hypothesis Testing 188 (43+145) of these probesets were thenmeasured in a set of independent clinical specimens including 19 adenomatissues and 19 cancer tissues. It was confirmed that 158 (30+128) of thetarget probesets (or probesets against the same gene locus) werelikewise differentially expressed (P<0.05) in theseindependently-derived tissues. Probesets elevated in adenoma and cancersrelative to each other are shown in Table 5 and Table 6 respectively.

It was further observed that 137 (33+104) gene loci are diagnosticallyuseful for discriminating colorectal adenomas and cancers relative toeach phenotype. The validation data included probesets designed tohybridise to 128 of these candidate gene symbols. It was observed that21 of the 31 genes elevated in adenomas relative to cancers werelikewise differentially expressed by at least one probeset. Of the 97gene symbols elevated in cancer relative to adenoma it was confirmedthat 89 gene symbols demonstrated at least one probeset in thevalidation data to be likewise differentially expressed. The validationtesting of the adenoma and cancer elevated gene loci is shown in Table 7and Table 8, respectively.

Conclusion

It was concluded that the candidate probesets shown in FIXME aredifferentially expressed between adenomatous and adenocarcinoma tissuesand thus useful for distinguishing these tissues. Gene transcripts thathybridise to these probesets are thus diagnostically informative in aclinical setting to classify such neoplastic tissues.

EXAMPLE 5 Materials and Methods for Examples 2 To 3

Gene expression profiling data measured in 454 colorectal tissuespecimens including neoplastic, normal and non-neoplastic diseasecontrols was purchased from GeneLogic Inc (Gaithersburg, Md. USA). Foreach tissue specimen an Affymetrix (Santa Clara, Calif. USA)oligonucleotide microarray data totalling 44,928 probesets (HGU133A &HGU133B, combined), experimental and clinical descriptors, and digitallyarchived microscopy images of histological preparations was received.Prior to applying discovery methods to these data extensive qualitycontrol methods were carried out, including statistical exploration,review of clinical records for consistency and histopathology audit of arandom sample of arrays. Microarrays that did not meet acceptablequality criteria were removed from the analysis.

Hypothesis Testing

Candidate transcription biomarkers were tested using a customoligonucleotide microarray of 25-mer oligonucleotide probesets designedto hybridise to candidate RNA transcripts identified during discovery.Differential expression hypotheses were tested using RNA extractsderived from independently collected clinical samples comprising 30normal colorectal tissues, 19 colorectal adenoma tissues, and 19colorectal adenocarcinoma tissues. Each RNA extract was confirmed tomeet strict quality control criteria.

Colorectal Tissue Specimens

All tissues used for hypothesis testing were obtained from a tertiaryreferral hospital tissue bank in metropolitan Adelaide, Australia(Repatriation General Hospital and Flinders Medical Centre). Access tothe tissue bank for this research was approved by the Research andEthics Committee of the Repatriation General Hospital and the EthicsCommittee of Flinders Medical Centre. Informed patient consent wasreceived for each tissue studied.

Following surgical resection, specimens were placed in a sterilereceptacle and collected from theatre. The time from operative resectionto collection from theatre was variable but not more than 30 minutes.Samples, approximately 125 mm3 (5×5×5 mm) in size, were taken from themacroscopically normal tissue as far from pathology as possible, definedboth by colonic region as well as by distance either proximal or distalto the pathology. Tissues were placed in cryovials, then immediatelyimmersed in liquid nitrogen and stored at −150C until processing.

RNA extraction

RNA extractions were performed using Trizol(R)reagent (Invitrogen,Carlsbad, Calif., USA) as per manufacturer's instructions. Each samplewas homogenised in 300 μL of Trizol reagent using a modified Dremeldrill and sterilised disposable pestles. An additional 200 μL of Trizolreagent was added to the homogenate and samples were incubated at RT for10 minutes. 100 μL of chloroform was then added, samples were shakenvortexed for 15 seconds, and incubated at RT for 3 further minutes. Theaqueous phase containing target RNA was obtained by centrifugation at12,000 rpm for 15 min, 40 C. RNA was then precipitated by incubatingsamples at RT for 10 min with 250 μL of isopropanol. Purified RNAprecipitate was collected by centrifugation at 12,000 rpm for 10minutes, 40 C. and supernatants were discarded. Pellets were then washedwith 1 mL 75% ethanol, followed by vortexing and centrifugation at7,500g for 8 min, 40 C. Finally, pellets were air-dried for 5 min andresuspended in 80 μL of RNase free water. To improve subsequentsolubility samples were incubated at 55° C. for 10 min. RNA wasquantified by measuring the optical density at A260/280 nm. RNA qualitywas assessed by electrophoresis on a 1.2% agarose formaldehyde gel.

Gene Chip Processing

To test hypotheses related to biomarker candidates for colorectalneoplasia RNA extracts were assayed using a custom GeneChip designed incollaboration with Affymetrix (Santa Clara, Calif. USA). These customGeneChips were processed using the standard Affymetrix protocoldeveloped for the HU Gene ST 1.0 array described in (Affy:WTAssay).

Statistical software and Data Processing

The R statistics environment R and BioConductor libraries (BioConductor,www.bioconductor.org) (BIOC) were used for most analyses. To mapprobeset IDs to gene symbol on the Custom GeneChip, hgu133plus2 libraryversion 2.2.0, which was assembled using Entrez Gene data downloaded onApr 18 12:30:55 2008 (BIOC) was used.

Hypothesis Testing of Differentially Expressed Biomarkers

To assess differential expression between tissue classes, the Student'st test for equal means between two samples or the robust variantprovided by the limma library (Smyth)(limma) was used. The impact offalse discovery due to multiple hypothesis testing was mitigated byapplying a Bonferroni adjustment to P values in the discovery process(MHT:Bonf). For hypotheses testing the slightly less conservativemultiple hypothesis testing correction of Benjamini & Hochberg, whichaims to control the false discovery rate of solutions(MHT:BH) wasapplied.

Discovery of Tissue-Specific Gene Expression Patterns

Discovery methods using gene expression data often yield numerouscandidates, many of which are not suitable for commercial productsbecause they involve subtle gene expression differences that would bedifficult to detect in laboratory practice. Pepe et al. note that the‘ideal’ biomarker is detectable in tumor tissue but not detectable (atall) in non-tumour tissue (Pepe:biomarker:development.) To bias towardcandidates that meet this criterion, an analysis method was developedthat aims to enrich the candidates for biomarkers whose qualitativeabsence or presence measurement is diagnostic for the phenotype ofinterest. This method attempts to select candidates that show aprototypical ‘turned-on’ or ‘turned-off’ pattern relative to an estimateof the background/noise expression across the chip. Such RNA transcriptsare more likely to correlate with downstream translated proteins withdiagnostic potential or to predict upstream genomic changes (e.g.methylation status) that can be used diagnostically. This focus onqualitative rather than quantitative outcomes may simplify the productdevelopment process for such biomarkers.

The method is based on the assumption that the pool of extracted RNAspecies in any given tissue (e.g. colorectal mucosae) will specificallybind to a relatively small subset of the full set of probesets on aGeneChip designed to measure the whole genome. On this assumption, it isestimated that most probesets on a full human gene chip will not exhibitspecific, high-intensity signals.

This observation is utilised to approximate the background or‘non-specific binding’ across the chip by choosing a theoretical levelequal to the value of e.g. lowest 30% quantile of the ranked meanvalues. This quantile can be arbitrarily set to some level below which areasonable assumption is made that the signals do not representabove-background RNA binding. Finally, this background estimate is usedas a threshold to estimate the ‘OFF’ probesets in an experiment for,say, the non-neoplastic tissue specimens.

Conversely, probesets which are 1) expressed above this theoreticalthreshold level and 2) at differentially higher levels in the tumourspecimens may be a tumour specific candidate biomarker. In this case theconcept of ‘fold-change’ thresholds can also be conveniently applied tofurther emphasize the concept of absolute expression increases in aputatively ‘ON’ probeset.

Given the assumption of low background binding for a sizeable fractionof the measured probesets, this method was only used in the largeGeneLogic data and discovery. To construct a filter for hypothetically‘turned on’ biomarkers in the GeneLogic discovery data, the meanexpression level for all 44,928 probesets was first estimated across thefull range of 454 tissues. The 44,928 mean values were then ranked andthe expression value equivalent to the 25th percentile across thedataset calculated. This arbitrary threshold was chosen because it wastheorized that the majority of transcripts (and presumably more than25%) in a given specimen should exhibit low concentration whicheffectively transcriptional silence. Thus this threshold represents aconservative upper bound for what is estimated as non-specific, orbackground, expression.

EXAMPLE 6 Determine Gene Identity of a Nucleic Acid Sequence of Interestwhich is Define by an Affymetrix Probeset

BLAST the sequence of interest using online available Basic LocalAlignment Search Tools [BLAST]. e.g. NCBI/BLAST

-   -   (http://blast.ncbi.nlm.nih.gov/Blast.cgi)    -   (a) Select “Human” in BLAST ASSEMBLED GENOMES on the web page        http://blast.ncbi.nlm.nih.gov/Blast.cgi    -   (b) Leave the default settings, i.e.:        -   Database: Genome (all assemblies)        -   Program: megaBLAST: compare highly related nucleotide            sequences        -   Optional parameters: Expect: 0.01, Filter: default,            Descriptions: 100, Alignments: 100    -   (c) Copy/Paste Sequence into the “BLAST” window    -   (d) Click “Begin Search”    -   (e) Click “View Report”

Assessment of the Open BLAST Search Results

Multiple significant sequence alignments may be identified when“blasting” the sequence.

Identify Gene Nomenclature of the Identified Sequence Match

-   -   (a) Click the link to one of the identified hits    -   (b) The new page will schematically depict the position of the        hit on one chromosome. It will be apparent which gene is hit.    -   (c) Retrieve the “hit” sequence clicking on the link    -   (d) Do a search for the gene in the provided “search” window.        This provides the gene nucleotide coordinates for the gene.

Determine Promiscuity of Sequence

-   -   (a) Open the NCBI/BLAST tool,        (http://blast.ncbi.nlm.nih.gov/Blast.cgi)    -   (b) Click on “nucleotide Blast” under “basic BLAST”    -   (c) Copy/paste the sequence of interest into the “Query        Sequence” window    -   (d) Click “Blast”.

Assessment of the nBLAST Search Results of the Sequence

-   -   (a) The nBLAST exercise with the Sequence may result in multiple        Blast hits of which some accession entry numbers are listed in        “Description”.    -   (b) These hits should be reviewed.

Determine Location of the Sequence in the Gene

The Ensembl database is an online database, which produces and maintainsautomatic annotation selected eukaryotic genomes(www.ensembl.orq/index.html)

Identify Location of the Sequence in the Gene

-   -   (a) Set “Search” to Homo Sapiens, Type “the gene name” in the        provided Search Field Ensemble.org/index.html)    -   (b) Click “Go”    -   (c) Click the “vega protein_coding Gene: OTTHUMG000000144184”        link to get an annotation report    -   (d) Click on “Gene DAS Report” to retrieve information regarding        Alternative splice site database: Type “the gene name” in search        field        -   Click on “the gene entry”        -   Scroll down to “evidence”        -   Review alternative splice sites        -   Click “Confirmed intron/exons” to get a list of coordinates            for the exons & introns.

Alternative Splicing and/or Transcription

The AceView Database provides curated and non-redundant sequencerepresentation of all public mRNA sequences. The database is availablethrough NCBI: http;//www.ncbi.nlm.nih.gov/IEB/Research/Acembly/

Further Investigation of the Gene mRNA Transcripts

-   -   (a) Type “the gene name” into the provided “search” field    -   (b) Click “Go”    -   (c) The following information is available from the resulting        entry in AceView:        -   The number of cDNA clones from which the gene is constructed            (ie originated-from experimental work involving isolation of            mRNA)        -   The mRNAs predicted to be produced by the gene        -   The existence of non-overlapping alternative exons and            validated alternative polyadenylation sites        -   The existence of truncations        -   The possibility of regulated alternate expression        -   Introns recorded as participating in alternatively splicing            of the gene    -   (d) Classic splice site motives

Application of Method to LOC643911/hCG_1815491

Materials and Methods

Extraction of RNA

RNA extractions were performed using Trizol(R) reagent (Invitrogen,Carlsbad, Calif., USA) as per manufacturer's instructions. Each samplewas homogenised in 300 μL of Trizol reagent using a modified dremeldrill and sterilised disposable pestles. Additional 200 μL of Trizolreagent was added to the homogenate and samples were incubated at RT for10 minutes. 100 μL of chloroform was then added, samples were shakenvortexed for 15 seconds, and incubated at RT for 3 further minutes. Theaqueous phase containing target RNA was obtained by centrifugation at12,000 rpm for 15 min, 40° C. RNA was then precipitated by incubatingsamples at RT for 10 min with 250 μL of isopropanol. Purified RNAprecipitate was collected by centrifugation at 12,000 rpm for 10minutes, 40. C and supernatants were discarded. Pellets were then washedwith 1 mL 75% ethanol, followed by vortexing and centrifugation at 7,500g for 8 min, 40° C. Finally, pellets were air-dried for 5 min andresuspended in 80 μL of RNase free water. To improve subsequentsolubility samples were incubated at 55° C. for 10 min. RNA wasquantified by measuring the optical density at A260/280 nm. RNA qualitywas assessed by electrophoresis on a 1.2% agarose formaldehyde gel.

Gene Chip Processing

RNA samples to analyze on Human Exon 1.0 ST GeneChips were processedusing the Affymetrix WT target labeling and control kit (part# 900652)following the protocol described in (Affymetrix 2007 P/N 701880 Rev.4).Briefly: First cycle cDNA was synthesized from 100 ng ribosomal reducedRNA using random hexamer primers tagged with T7 promoter sequence andSuperScript II (Invitrogen, Carlsbad Calif.), this was followed by DNAPolymerase I synthesis of the second strand cDNA. Anti-sense cRNA wasthen synthesized using T7 polymerase. Second cycle sense cDNA was thensynthesised using SuperScript II, dNTP+dUTP, and random hexamers toproduce sense strand cDNA incorporating uracil. This single strandeduracil containing cDNA was then fragmented using a combination of uracilDNA glycosylase (UDG) and apurinic/apyrimidinic endonuclease1 (APE 1).Finally the DNA was biotin labelled using terminal deoxynucleotidyltransferase (TdT) and the Affymetrix proprietary DNA Labeling reagent.Hybridization to the arrays was carried out at 45° C. for 16-18hours.

Washing and staining of the hybridized GeneChips was carried out usingthe Affymetrix Fluidics Station 450 and scanned with the AffymetrixScanner 3000 following recommended protocols.

SYBR Green Based Quantitative Real Time-PCR

Quantitative real time polymerase chain reaction was performed on RNAisolated from clinical samples for the amplification and detection ofthe various hCG_1815491 transcripts.

Firstly cDNA was synthesized from 2ug of total RNA using the AppliedBiosystems High Capacity Reverse transcription Kit (P/N 4368814). Aftersynthesis the reaction was diluted 1:2 with water to obtain a finalvolume of 40 ul and 1 ul of this diluted cDNA used in subsequent PCRreactions.

PCR was performed in a 25 ul volume using 12.5 ul Promega 2× PCR mastermix (P/N M7502), 1.5 ul 5 uM forward primer, 1.5 ul 5 uM reverse primer,7.875 ul water, 0.625 ul of a 1:3000 dilution of 10,000× stock of SYBRgreen 1 pure dye (Invitrogen P/N S7567), and 1 ul of cDNA.

Cycling conditions for amplification were 95° for 2minutes×1 cycle, 95°for 15 seconds and 60° for 1 minute×40 cycles. The amplificationreactions were performed in a Corbett Research Rotor-Gene RG3000 or aRoche LightCycler480 real-time PCR machine. When the RocheLightCycler480 real-time PCR machine was used for amplification thereaction volume was reduced to 10 ul and performed in a 384 well platebut the relative ratios between all the components remained the same.Final results were calculated using the ΔΔCt method with the expressionlevels of the various hCG_1815491 transcripts being calculated relativeto the expression level of the endogenous house keeping gene HPRT.

End-Point PCR

End point PCR was performed on RNA isolated from clinical samples forthe various hCG_1815491 transcripts. Conditions were identical to thosedescribed for the SYBR green assay above but with the SYBR green dyebeing replaced with water. The amplification reactions were performed ina MJ Research PTC-200 thermal cycler. 2.5 μl of the amplified productswere analysed on 2% agarose E-gel (Invitrogen) along with a 100-basepair DNA Ladder Marker.

Results

The nucleotide structure and expression levels of transcripts related tohCG_1815491 was analysed based on the identification of diagnosticutility of Affymetrix probesets 238021_s_at and 238022_at from the genechip analysis.

The gene hCG_1815491 is currently represented in NCBI as a single RefSeqsequence, XM_93911. The RefSeq sequence of hCG_1815491 is based on 89GenBank accessions from 83 cDNA clones. Prior to March 2006, theseclones were predicted to represent two overlapping genes, LOC388279 andLOC650242 (the latter also known as LOC643911). In March 2006, the humangenome database was filtered against clone rearrangements, co-alignedwith the genome and clustered in a minimal non-redundant way. As aresult, LOC388272 and LOC650242 were merged into one gene namedhCG_1815491 (earlier references to hCG_1815491 are: LOC388279,LOC643911, LOC650242, XM_944116, AF275804, XM_373688). It has beendetermined that the Ref Sequence, which is defined by the genomiccoordinates 8579310 to 8562303 on human chromosome 16 as defined by theNCBI contig reference NT_010498.15|Hs16_10655, NCBI 36 March 2006 genomeencompasses hCG_1815491. The 10 predicted RNA variants derived from thisgene have been aligned with the genomic nucleotide sequence residing inthe map region 8579310 to 8562303. This alignment analysis revealed theexistence of at least 6 exons of which several are alternativelyspliced. The identified exons are in contrast to the just 4 exonsspecified in the NCBI hCG_1815491 RefSeq XM_93911. Two additionalputative exons were also identified in the Ref Sequence by examinationof included probesets on Affymetrix Genechip HuGene Exon 1.0 that targetnucleotide sequences embedded in the Ref Sequence. The identified andexpanded exon-intron structure of hCG_1815491 have been used to designspecific oligonucleotide primers, which allowed measurement of theexpression of RNA variants generated from the Ref Sequence by usingPCR-based methodology (FIG. 4)

EXAMPLE 7

Immunohistochemistry is a useful method for evaluating changes in localexpression of up or down-regulated markers in human tissue.

Materials and Methods:

Four micrometre sections were incubated in a universal decloaking bufferfor 75 minutes at 80 μL to expose masked epitopes. Protein expressionwas determined using an antibody targeting the C-terminal domain ofMesothelin (MSLN) on colonic biopsies from 30 patients (10 normals, 10cancers, 10 adenomas). Antibodies were applied for one hour at roomtemperature. After washing, sections were incubated with polymerichorse-radish peroxidase. Antibody localization was visualized using 3′3′diaminobenzidine.

Result:

There was a marked upregulation of MSLN in the adenoma and cancertissues compared to the normal controls. The normal tissues showed mildstaining for MSLN in the cytoplasm of the colonic epithelium but thecancer and particularly the adenomas tissues shows significantupregulation of MSLN in their multilayered epithelium. This upregulationwas observed in all 10 adenomas tissue and in 9 out of the 10 cancertissues. These patterns of staining are illustrated in FIGS. 4, 5 and 6.

Conclusion:

Elevated expression of MSLN has been detected in colon neoplasia,confirming the upregulation observed in the mRNA expression data andverifying the diagnostic utility of both the MSLN mRNA and protein fordetection of colorectal neoplasia.

EXAMPLE 8 Evidence of MMP3 Protein Expression in Stools of Patients withColorectal Neoplasia

Affymetrix probeset designated 205828_at was identified to be expressedhigher in 190 neoplastic tissue specimens relative to 264 non-neoplasticspecimens. The probeset 205828_at hybridizes to RNA transcribed from thegene encoding Matrix Metalloproteinase 3 (MMP3) NM_002422. Thedifferential expression profile of probeset 205828_at was furtherdemonstrated by profiling RNA collected from 68 independent clinicalspecimens comprising 19 adenomas, 19 adenocarcinomas and 30 non-diseasecontrols, FIG. 7.

Materials and Methods

A commercially available bead-suspension immunoassay targeting theprotein MMP3 was purchased from R&D Systems (MMP Kit reagents LMP000 andLMP513) to measure MMP3 concentration in stools of human patientsdiagnosed with colorectal neoplasia. Proteins were extracted from stoolspecimens using a phosphate buffered saline wash from 6 non-diseasecontrols, 10 adenoma and 11 adenocarcinoma subjects. The resultingprotein extracts were analyzed using the Luminex bead-based suspensionMMP3 assay as recommended by manufacturer.

Results

An elevated endogenous expression of MMP3 was observed in stoolspecimens from patients diagnosed with colon adenomas or adenocarcinomasrelative to non-neoplastic controls (FIG. 8).

Conclusion

Measurement of MMP3 protein in bodily fluids such as stool samples isuseful for diagnosing colorectal neoplasia.

Tables

Probeset designations include both HG-133plus2 probeset IDs and HumanGene 1.0 ST array probe ids. The latter can be conveniently mapped toTranscript Cluster ID using the Human Gene 1.0ST probe tab file providedby Affymetrix(http://www.affymetrix.com/Auth/analysis/downloads/na22/wtgene/HuGene-1_0-st-v1.probe.tab.zip).Using publicly available software such as NetAffx (provided byAffymetrix), the Transcript Cluster ID may be further mapped to genesymbol, chromosomal location, etc.

Table 1.

Probesets demonstrated to be expressed higher in neoplastic tissuesrelative to non-neoplastic controls. TargetPS: Affymetrix HG-U133plus2probeset id; Symbol: putative gene symbol corresponding to targetprobeset id—multiple symbol names indicate the possibility of probesethybridisation to multiple gene targets; Signif. FDR: Adjusted p-valuefor mean difference testing between RNA extracted from neoplasia andnon-neoplastic tissues. Adjustment is made using Benjamini & Hochbergcorrection for multiple hypothesis testing (Benjamini and Hochberg,1995); D.value50: Diagnostic effectiveness parameter estimatecorresponding to the area of a receiver operator characteristic ROC.This parameter provides a convenient estimate of diagnostic utility andis described in (Saunders, 2006); FC: fold change between meanexpression level of neoplasia vs. non-neoplasia; Sens-Spec: Estimate ofdiagnostic performance corresponding to the ROC curve pointdemonstrating equal sensitivity and specificity; CI (95): 95% confidenceinterval of sensitivity and specificity estimates.

Table 2.

Evidence of multiple probesets which correspond to gene symbols claimedherein exhibiting RNA concentration differences between neoplasia andnon-neoplastic controls. Symbol: gene symbol; ValidPS_UP: Affymetrixprobeset IDs demonstrating statistically significant overexpression inneoplastic RNA extracts relative to non-neoplastic controls. Signif.FDR: Adjusted p-value for mean difference testing between RNA extractedfrom neoplasia and non-neoplastic tissues. Adjustment is made usingBenjamini & Hochberg correction for multiple hypothesis testing(Benjamini and Hochberg, 1995); D.value50: Diagnostic effectivenessparameter estimate corresponding to the area of a receiver operatorcharacteristic ROC. This parameter provides a convenient estimate ofdiagnostic utility and is described in (Saunders, 2006); FC: fold changebetween mean expression level of neoplasia vs. non-neoplasia; Sens-Spec:Estimate of diagnostic performance corresponding to the ROC curve pointdemonstrating equal sensitivity and specificity; CI (95): 95% confidenceinterval of sensitivity and specificity estimates.

Example 2

Table 3.

Probesets which demonstrate a qualitatively (in addition toquantitative) elevated profile in neoplastic tissues relative tonon-neoplastic controls. TargetPS: Affymetrix HG-U133plus2 probeset id;Symbol: putative gene symbol corresponding to target probesetid—multiple symbol names indicate the possibility of probesethybridisation to multiple gene targets; Signif. FDR: Adjusted p-valuefor mean difference testing between RNA extracted from neoplasia andnon-neoplastic tissues. Adjustment is made using Benjamini & Hochbergcorrection for multiple hypothesis testing (Benjamini and Hochberg,1995); D.value50: Diagnostic effectiveness parameter estimatecorresponding to the area of a receiver operator characteristic ROC.This parameter provides a convenient estimate of diagnostic utility andis described in (Saunders, 2006); FC: fold change between meanexpression level of neoplasia vs. non-neoplasia; Sens-Spec: Estimate ofdiagnostic performance corresponding to the ROC curve pointdemonstrating equal sensitivity and specificity; CI (95): 95% confidenceinterval of sensitivity and specificity estimates.

Table 4.

Evidence of multiple probesets which correspond to gene symbols claimedherein exhibiting qualitative changes in RNA concentration in neoplastictissues. Symbol: gene symbol; ValidPS_UP: Affymetrix probeset IDsdemonstrating statistically significant overexpression in neoplastic RNAextracts relative to non-neoplastic controls. Signif. FDR: Adjustedp-value for mean difference testing between RNA extracted from neoplasiaand non-neoplastic tissues. Adjustment is made using Benjamini &Hochberg correction for multiple hypothesis testing (Benjamini andHochberg, 1995); D.value50: Diagnostic effectiveness parameter estimatecorresponding to the area of a receiver operator characteristic ROC.This parameter provides a convenient estimate of diagnostic utility andis described in (Saunders, 2006); FC: fold change between meanexpression level of neoplasia vs. non-neoplasia; Sens-Spec: Estimate ofdiagnostic performance corresponding to the ROC curve pointdemonstrating equal sensitivity and specificity; CI (95): 95% confidenceinterval of sensitivity and specificity estimates.

Table 5

Probesets demonstrated to be expressed higher in adenoma tissuesrelative to cancer tissues. TargetPS: Affymetrix HG-U133plus2 probesetid; Symbol: putative gene symbol corresponding to target probesetid—multiple symbol names indicate the possibility of probesethybridisation to multiple gene targets; Signif. FDR: Adjusted p-valuefor mean difference testing between RNA extracted from neoplasia andnon-neoplastic tissues. Adjustment is made using Benjamini & Hochbergcorrection for multiple hypothesis testing (Benjamini and Hochberg,1995); D.value50: Diagnostic effectiveness parameter estimatecorresponding to the area of a receiver operator characteristic ROC.This parameter provides a convenient estimate of diagnostic utility andis described in (Saunders, 2006); FC: fold change between meanexpression level of adenomas vs. cancers; Sens-Spec: Estimate ofdiagnostic performance corresponding to the ROC curve pointdemonstrating equal sensitivity and specificity; CI (95): 95% confidenceinterval of sensitivity and specificity estimates.

Table 6

Probesets demonstrated to be expressed higher in cancer tissues relativeto adenoma tissues. TargetPS: Affymetrix HG-U133plus2 probeset id;Symbol: putative gene symbol corresponding to target probesetid—multiple symbol names indicate the possibility of probesethybridisation to multiple gene targets; Signif. FDR: Adjusted p-valuefor mean difference testing between RNA extracted from neoplasia andnon-neoplastic tissues. Adjustment is made using Benjamini & Hochbergcorrection for multiple hypothesis testing (Benjamini and Hochberg,1995); D.value50: Diagnostic effectiveness parameter estimatecorresponding to the area of a receiver operator characteristic ROC.This parameter provides a convenient estimate of diagnostic utility andis described in (Saunders, 2006); FC: fold change between meanexpression level of cancer tissues vs. adenoma tissues; Sens-Spec:Estimate of diagnostic performance corresponding to the ROC curve pointdemonstrating equal sensitivity and specificity; CI (95): 95% confidenceinterval of sensitivity and specificity estimates.

Table 7

Evidence of multiple probesets which correspond to gene symbols claimedherein exhibiting RNA concentration differences between adenoma andcancer tissues. Symbol: gene symbol; ValidPS_UP: Affymetrix probeset IDsdemonstrating statistically significant overexpression in neoplastic RNAextracts relative to non-neoplastic controls. Signif. FDR: Adjustedp-value for mean difference testing between RNA extracted from neoplasiaand non-neoplastic tissues. Adjustment is made using Benjamini &Hochberg correction for multiple hypothesis testing (Benjamini andHochberg, 1995); D.value50: Diagnostic effectiveness parameter estimatecorresponding to the area of a receiver operator characteristic ROC.This parameter provides a convenient estimate of diagnostic utility andis described in (Saunders, 2006); FC: fold change between meanexpression level of adenoma tissues vs. cancer tissues; Sens-Spec:Estimate of diagnostic performance corresponding to the ROC curve pointdemonstrating equal sensitivity and specificity; CI (95): 95% confidenceinterval of sensitivity and specificity estimates.

Table 8

Evidence of multiple probesets which correspond to gene symbols claimedherein exhibiting RNA concentration differences between cancer andadenoma tissues. Symbol: gene symbol; ValidPS_UP: Affymetrix probesetIDs demonstrating statistically significant overexpression in neoplasticRNA extracts relative to non-neoplastic controls. Signif. FDR: Adjustedp-value for mean difference testing between RNA extracted from neoplasiaand non-neoplastic tissues. Adjustment is made using Benjamini &Hochberg correction for multiple hypothesis testing (Benjamini andHochberg, 1995); D.value50: Diagnostic effectiveness parameter estimatecorresponding to the area of a receiver operator characteristic ROC.This parameter provides a convenient estimate of diagnostic utility andis described in (Saunders, 2006); FC: fold change between meanexpression level of cancer tissues vs. adenoma tissues; Sens-Spec:Estimate of diagnostic performance corresponding to the ROC curve pointdemonstrating equal sensitivity and specificity; CI (95): 95% confidenceinterval of sensitivity and specificity estimates.

Those skilled in the art will appreciate that the invention describedherein is susceptible to variations and modifications other than thosespecifically described. It is to be understood that the inventionincludes all such variations and modifications. The invention alsoincludes all of the steps, features, compositions and compounds referredto or indicated in this specification, individually or collectively, andany and all combinations of any two or more of said steps or features.

TABLE 1 Signif. D.val Sens- TargetPS Symbol FDR 5 FC Spec CI (95)203256_at CDH3 3.75E−31 4.2476 37.54 98.3 95.5-99.5 200660_atS100A11:LOC730558: 2.68E−27 3.8969 3.83 97.4 93.9-99.1LOC730278:LOC729659 201341_at ENC1 1.44E−26 3.667 3.93 96.7 92.6-98.7212063_at MAPK10:CD44 3.35E−26 3.7161 7.06 96.8 92.9-98.8 217523_atMAPK10:CD44 3.35E−26 3.7151 7.06 96.8 92.9-98.8 201563_at SORD 3.44E−253.4659 4.36 95.8 91.3-98.3 202431_s_at LOC731404: 5.19E−25 3.6014 4.1196.4 92.2-98.6 LOC729194:MYC 221577_x_at GDF15 5.51E−25 3.5554 5.84 96.291.8-98.5 204702_s_at LOC650331:NFE2L3: 1.51E−24 3.52 4.57 96.191.6-98.4 LOC642996 203961_at NEBL 5.41E−24 3.5292 5.52 96.1 91.7-98.4203962_s_at NEBL 5.41E−24 3.5295 5.52 96.1 91.7-98.4 201338_x_at GTF3A1.74E−22 3.2283 2.92 94.7 89.6-97.6 215091_s_at GTF3A 1.74E−22 3.22832.92 94.7 89.5-97.6 207850_at CXCL2:CXCL3 5.76E−22 3.2874 7.85 95  90-97.8 222549_at CLDN1 6.10E−22 3.2561 13.09 94.8 89.7-97.7 204259_atMMP7 7.61E−22 3.2624 69.29 94.9 89.8-97.7 228754_at SLC6A6:LOC7287211.15E−21 3.2282 5.02 94.7 89.5-97.6 209774_x_at CXCL2:CXCL3 1.88E−213.2884 7.85 95   90-97.8 218872_at TESC 3.26E−21 3.2134 16.84 94.689.5-97.6 212942_s_at KIAA1199 8.12E−21 3.0489 25.16 93.6 88-97209369_at ANXA3 1.15E−20 3.0417 3.34 93.6 87.9-97   204404_at SLC12A21.40E−20 3.0281 3.42 93.5 87.9-96.9 225835_at SLC12A2 1.40E−20 3.02613.42 93.5 87.8-96.9 219911_s_at SLCO4A1 1.46E−20 3.0968 4.84 93.988.4-97.2 203510_at MET 1.50E−20 3.0806 3.35 93.8 88.3-97.1 202936_s_atSOX9 1.63E−20 3.0982 3.85 93.9 88.4-97.2 201416_at SOX4 2.30E−20 3.01792.89 93.4 87.8-96.9 201417_at SOX4 2.30E−20 3.0146 2.89 93.4 87.7-96.9208712_at CCND1 7.06E−20 2.9082 2.85 92.7 86.7-96.4 204351_at S100P4.56E−19 2.9463 4.37 93 87.1-96.6 227475_at FOXQ1 4.85E−19 2.9494 10.9793 87.1-96.6 205983_at DPEP1 5.27E−19 2.8878 23.9 92.6 86.6-96.3204470_at CXCL2:CXCL1 5.53E−19 2.9257 10.4 92.8 86.8-96.5 212531_at LCN25.68E−19 2.9407 14.6 92.9   87-96.5 217867_x_at BACE2 5.87E−19 2.90423.8 92.7 86.7-96.4 228915_at DACH1 1.05E−18 2.9218 5.81 92.8 86.9-96.5218704_at RNF43 2.12E−18 2.9218 3.24 92.8 86.9-96.5 202504_at TRIM292.36E−18 2.8231 11.01 92.1 85.9-96   241031_at NLF1 3.12E−18 2.7999 8.1291.9 85.6-95.9 201195_s_at SLC7A5:LAT1-3TM 5.11E−18 2.7562 6.31 91.685.2-95.7 201656_at ITGA6 7.38E−18 2.6842 2.62 91 84.5-95.3 229215_atASCL2 7.76E−18 2.7573 7.73 91.6 85.3-95.7 217996_at PHLDA1 1.34E−172.7007 5.27 91.2 84.6-95.4 205476_at CCL20 2.03E−17 2.6222 10.14 90.583.8-94.9 226360_at ZNRF3 2.03E−17 2.7245 4.91 91.3 84.9-95.6 219956_atGALNT6:ELA1 2.90E−17 2.682 5.27 91 84.4-95.3 201506_at TGFBI 4.14E−172.6863 4.31 91 84.5-95.3 212070_at GPR56 7.45E−17 2.5866 2.6 90.283.5-94.7 212281_s_at LOC731966: 1.88E−16 2.583 2.77 90.2 83.4-94.7LOC729599: TMEM97 202831_at GPX2 4.00E−16 2.397 3.56 88.5 81.2-93.5225541_at LOC442108: 4.37E−16 2.5983 4.19 90.3 83.5-94.8 RPL22L1218984_at PUS7:LOC730279 5.26E−16 2.6006 3.06 90.3 83.6-94.8 219630_atPDZK1IP1 5.38E−16 2.506 4.22 89.5 82.5-94.2 202935_s_at FLJ376441.04E−15 2.4727 3.64 89.2 82.1-94   204401_at KCNN4 1.85E−15 2.4677 3.0789.1 82-94 222696_at AXIN2 1.90E−15 2.4301 4.44 88.8 81.6-93.7221923_s_at NPM1 2.22E−15 2.6018 2.18 90.3 83.5-94.8 201666_at TIMP12.44E−15 2.4295 3.01 88.8 81.6-93.7 210511_s_at INHBA 2.80E−15 2.51373.76 89.6 82.6-94.3 223062_s_at LOC651255:PSAT1: 3.32E−15 2.4895 5.5289.3 82.3-94.1 LOC389173: LOC729779:C8orf62 225520_at MTHFD1L 4.46E−152.4846 4.04 89.3 82.3-94.1 206224_at CST1 7.04E−15 2.4174 13.01 88.781.5-93.6 201014_s_at PAICS 1.19E−14 2.3935 2.49 88.4 81.3-93.5209309_at AZGP1:LOC401393 1.31E−14 2.3949 6.19 88.4 81.2-93.5 218796_atC20orf42 1.38E−14 2.4561 2.78 89   82-93.9 60474_at C20orf42 1.38E−142.4547 2.78 89 81.9-93.9 219787_s_at ECT2 1.42E−14 2.4283 2.82 88.881.6-93.7 231832_at WDR51B:GALNT4 1.79E−14 2.4259 2.12 88.7 81.6-93.7218507_at HIG2 2.50E−14 2.3654 4.25 88.2 80.9-93.3 202286_s_at TACSTD23.13E−14 2.3701 15.71 88.2 80.9-93.3 205513_at TCN1 4.81E−14 2.301915.22 87.5 80.1-92.8 224428_s_at CDCA7:LOC442172 6.41E−14 2.2662 4.2787.1 79.6-92.5 203124_s_at SLC11A2 7.07E−14 2.3616 2.18 88.1 80.8-93.3224915_x_at TALDO1:C20orf199 8.45E−14 2.2732 2.87 87.2 79.7-92.6226227_x_at TALDO1:C20orf199 8.45E−14 2.2707 2.87 87.2 79.7-92.6226835_s_at TALDO1:C20orf199 8.45E−14 2.2746 2.87 87.2 79.7-92.6200832_s_at SCD:LOC651109: 1.23E−13 2.2759 4.28 87.2 79.8-92.6 LOC645313204170_s_at CKS2 2.13E−13 2.2413 4.15 86.9 79.3-92.3 219682_s_at TBX33.27E−13 2.2498 4.94 87 79.4-92.4 203313_s_at TGIF 3.35E−13 2.175 2.1286.2 78.4-91.8 201601_x_at IFITM1 4.78E−13 2.0659 3.87 84.9   77-90.8214022_s_at IFITM1 4.78E−13 2.065 3.87 84.9   77-90.8 201328_at ETS25.23E−13 2.2182 2.36 86.6   79-92.2 201112_s_at CSE1L 7.98E−13 2.23362.28 86.8 79.2-92.2 210766_s_at CSE1L 7.98E−13 2.232 2.28 86.8 79.2-92.2205361_s_at TMEM23:PFDN4: 1.69E−12 2.2328 2.24 86.8 79.2-92.3 HDAC9218086_at NPDC1 2.66E−12 2.169 2.53 86.1 78.4-91.8 206286_s_atTDGF1:TDGF3 3.07E−12 2.1205 6.33 85.5 77.7-91.4 204855_at SERPINB54.80E−12 2.1265 10.36 85.6 77.8-91.4 203878_s_at MMP11 6.30E−12 2.09594.55 85.3 77.4-91.1 202833_s_at SERPINA1 7.12E−12 2.0804 3.43 85.177.1-91   211429_s_at SERPINA1 7.12E−12 2.0818 3.43 85.1 77.2-91  228303_at No Symbol 9.19E−12 2.1527 1.61 85.9 78.2-91.6 225767_at NoSymbol 9.19E−12 2.1514 1.614 85.9 78.1-91.6 226311_at No Symbol 9.19E−122.1527 1.61 85.9 78.1-91.6 226777_at No Symbol 9.19E−12 2.152 1.61 85.978.1-91.6 227140_at No Symbol 9.19E−12 2.152 1.61 85.9 78.1-91.6229802_at No Symbol 9.19E−12 2.1519 1.61 85.9 78.2-91.6 232151_at NoSymbol 9.19E−12 2.1534 1.61 85.9 78.1-91.6 213880_at LGR5 1.10E−112.0619 7.89 84.9 76.9-90.8 225295_at SLC39A10 2.32E−11 2.1227 1.93 85.677.7-91.3 205470_s_at KLK11 3.11E−11 2.0097 6.04 84.3 76.2-90.3205174_s_at QPCT 3.46E−11 2.0435 3.03 84.7 76.6-90.7 222449_at TMEPAI3.73E−11 2.0605 2.2 84.9   77-90.8 222450_at TMEPAI 3.73E−11 2.0616 2.284.9 76.9-90.9 238021_s_at LOC643911 3.73E−11 1.647 1.33 79.5 70.8-86.5227174_at WDR72 5.22E−11 1.9844 14.11 83.9 75.8-90.1 202779_s_atUBE2S:LOC731049, 5.62E−11 1.9821 2.4 83.9 75.8-90   UBE2S:LOC731049219727_at DUOX2 9.34E−11 1.9355 9.27 83.3 75.1-89.6 210445_at FABP61.28E−10 1.9366 3.01 83.4 75.1-89.6 205828_at MMP3 1.44E−10 1.8964 15.6382.8 74.6-89.2 218963_s_at KRT23 3.58E−10 1.8856 6.81 82.7 74.5-89.1223447_at REG4 5.97E−10 1.8052 7.75 81.7 73.2-88.3 238984_at REG45.97E−10 1.8036 7.75 81.6 73.3-88.3 204475_at MMP1 1.22E−09 1.8132 10.5981.8 73.4-88.3 228653_at RP5-875H10.1 1.33E−09 1.8788 1.99 82.674.3-89.1 204580_at MMP12 1.99E−09 1.7881 6.24 81.4   73-88.1 203895_atPLCB4 2.29E−09 1.8389 2.37 82.1 73.7-88.6 203896_s_at PLCB4 2.29E−091.8414 2.37 82.1 73.8-88.6 235210_s_at RPESP 2.38E−09 1.8005 9.07 81.673.2-88.2 201468_s_at NQO1 2.68E−09 1.6978 2.62 80.2 71.6-87.1210519_s_at NQO1 2.68E−09 1.6973 2.62 80.2 71.6-87   222608_s_at ANLN4.94E−09 1.7543 2.63 81 72.5-87.7 212344_at SULF1 9.70E−09 1.7754 1.7481.3 72.9-88   212353_at SULF1 9.70E−09 1.7777 1.74 81.3 72.9-88  212354_at SULF1 9.70E−09 1.7751 1.74 81.3 72.8-87.9 201925_s_at CD551.45E−08 1.7612 2.22 81.1 72.6-87.8 201926_s_at CD55 1.45E−08 1.76032.22 81.1 72.5-87.8 202954_at PAK3:UBE2C 1.74E−08 1.6455 2.82 79.570.9-86.4 209792_s_at KLK10 2.64E−08 1.6142 4.52 79 70.2-86.1205890_s_at UBD:GABBR1, UBD 4.07E−08 1.6362 6.59 79.3 70.6-86.3209773_s_at RRM2 4.25E−08 1.6077 2.25 78.9 70.2-86   234331_s_atFAM84A:LOC653602 5.97E−08 1.6031 1.73 78.9 70.1-86   206976_s_at HSPH16.17E−08 1.6476 1.85 79.5 70.8-86.5 202718_at IGFBP2 8.07E−08 1.63481.93 79.3 70.6-86.3 225664_at TMEM30A:COL12A1 9.48E−08 1.6379 3.16 79.470.7-86.3 231766_s_at TMEM30A:COL12A1 9.48E−08 1.6394 3.16 79.470.7-86.3 201261_x_at BGN 1.01E−07 1.5939 2.69 78.7 69.9-85.9213905_x_at BGN 1.01E−07 1.596 2.69 78.8 69.9-85.8 204127_at RFC31.25E−07 1.5497 2.25 78.1 69.2-85.3 207457_s_at C6orf21:LY6G6D, 1.34E−071.5549 6.64 78.2 69.3-85.4 C6orf21:LY6G6D, C6orf21:LY6G6D 210052_s_atTPX2 1.56E−07 1.6655 2.03 79.8 71.1-86.7 202859_x_at LOC652128:IGHG1:1.99E−07 1.6331 3.1 79.3 70.6-86.3 IGHM:IGHV4-31: LOC647189:IGHV1-69:IGHA1:IL8:EXOC7:SIX6: IGHD:IGH@:IGHG3: C12orf32:ZCWPW2:IFI6:IGHG4:IGHA2: IGHG2:RAC1 211506_s_at LOC652128:IGHG1: 1.99E−071.6324 3.1 79.3 70.6-86.4 IGHM:IGHV4-31: LOC647189:IGHV1-69:IGHA1:IL8:EXOC7: SIX6:IGHD:IGH@: IGHG3:C12orf32: ZCWPW2:IFI6:IGHG4:IGHA2: IGHG2:RAC1 205479_s_at PLAU 2.25E−07 1.5392 3.5 77.969.1-85.1 238017_at RDHE2 2.71E−07 1.5511 2.52 78.1 69.3-85.3 204320_atCOL11A1 2.93E−07 1.5718 2.6 78.4 69.6-85.6 37892_at COL11A1 2.93E−071.57 2.6 78.4 69.5-85.6 203213_at CDC2 3.58E−07 1.5342 2.72 77.8  69-85.1 210559_s_at CDC2 3.58E−07 1.5348 2.72 77.9   69-85.1 232252_atDUSP27 4.68E−07 1.5123 4.81 77.5 68.7-84.8 225799_at MGC4677, 7.40E−071.4933 2.04 77.2 68.3-84.6 MGC4677: LOC541471 206239_s_at SPINK11.70E−06 1.4816 2.74 77.1 68.1-84.5 225806_at C14orf94 2.40E−06 1.65421.19 79.6 70.9-86.5 204885_s_at MSLN 3.78E−06 1.4263 1.93 76.2 67.2-83.7202998_s_at ENTPD4:LOXL2 4.81E−06 1.3717 2.19 75.4 66.3-83   207158_atAPOBEC1 9.49E−06 1.3811 1.63 75.5 66.4-83.1 218211_s_at MLPH 1.16E−051.4176 1.47 76.1 67.1-83.6 205366_s_at HOXB6 1.33E−05 1.3346 1.87 74.865.7-82.5 225681_at CTHRC1 1.83E−05 1.2913 2.57 74.1 64.9-81.8 205815_atREG3A 2.22E−05 1.2228 12.09 73 63.8-80.9 214974_x_at CXCL5 2.79E−051.281 4.48 73.9 64.8-81.7 207173_x_at CDH11 3.44E−05 1.2644 2.25 73.664.4-81.5 209955_s_at IFIH1:FAP 6.66E−05 1.2544 2.33 73.5 64.3-81.3205886_at REG1B 8.08E−05 1.1731 13.15 72.1 62.8-80.1 205713_s_at COMP0.0001 1.1543 1.69 71.8 62.6-79.9 208079_s_at AURKA:STK6P 0.0001 1.11731.81 71.2 61.8-79.3 209218_at SQLE 0.0001 1.1362 2.69 71.5 62.2-79.6212190_at SERPINE2 0.0002 1.1279 1.9 71.4 62.1-79.5 219955_at L1TD10.0002 1.1579 2.36 71.9 62.6-79.9 236894_at L1TD1 0.0002 1.1598 2.3671.9 62.6-79.9 209875_s_at SPP1 0.0004 1.0666 3.32 70.3 60.9-78.5205910_s_at CEL 0.0006 1.0877 1.46 70.7 61.2-78.8 209752_at REG1A 0.00061.0018 10.93 69.2 59.8-77.5 213975_s_at LILRA1:LILRB1 0.0013 1.0772 1.5570.5 61.1-78.7 202310_s_at COL1A1 0.0018 1.007 2.5 69.3 59.9-77.5202311_s_at COL1A1 0.0018 1.0058 2.5 69.2 59.8-77.5 217430_x_at COL1A10.0018 1.006 2.5 69.3 59.9-77.5 221729_at COL5A2 0.0026 1.054 1.36 70.160.7-78.4 221730_at COL5A2 0.0026 1.0559 1.36 70.1 60.8-78.4 205825_atPCSK1 0.0029 1.107 1.48 71 61.6-79.2 203860_at PCCA 0.0038 0.9396 1.4268.1 58.6-76.5 224646_x_at RPS12:H19 0.0051 1.0213 1.47 69.5 60.1-77.8205941_s_at COL10A1 0.0143 0.8495 2.05 66.4   57-75.1 226237_at COL8A10.0254 0.8307 1.43 66.1 56.6-74.8 223970_at RETNLB 0.0304 0.8148 1.4765.8 56.3-74.4 205765_at CYP3A5:CYP3A7 0.0545 0.8252 1.58 66 56.4-74.6232176_at SLITRK6 0.0576 0.8693 1.31 66.8 57.3-75.4 232481_s_at SLITRK60.0576 0.8701 1.31 66.8 57.4-75.3 235976_at SLITRK6 0.0576 0.868 1.3166.8 57.4-75.3 200665_s_at SPARC 0.0684 0.6727 1.45 63.2 53.6-72  205927_s_at CTSE 0.0694 0.7488 1.83 64.6 55.1-73.3 214651_s_at HOXA90.0759 0.7491 1.41 64.6   55-73.3 204051_s_at SFRP4 0.0829 0.6983 1.2963.7 54.1-72.4 202404_s_at COL1A2: 0.1891 0.6492 1.9 62.7 53.1-71.6LOC728628 204620_s_at CSPG2 0.9788 0.1834 1.05 53.7 44-63 221731_x_atCSPG2 0.9788 0.183 1.05 53.6 44.1-63   203083_at THBS2 0.9844 0.27841.26 55.5   46-64.8 214235_at CYP3A5:CYP3A43: 0.9932 0.3165 1.16 56.346.7-65.6 CYP3A5P2

TABLE 2 Gene Signif. Sens- CI Symbol ValidPS_UP Symbol FDR D.val5 FCSpec (95) CDH3 802708-HuGene_st:280037-HuGene_st:1019645- CDH3 3.75E−314.2474 37.54 98.3 95.5-99.5 HuGene_st:119416-HuGene_st:642035-HuGene_st:665706-HuGene_st:249831- HuGene_st:604066-HuGene_st:260528-HuGene_st:166615-HuGene_st:411984- HuGene_st:520679-HuGene_st:1071177-HuGene_st:988525-HuGene_st:317603- HuGene_st:301020-HuGene_st:693824-HuGene_st:468436-HuGene_st:203256_at:265728-HuGene_st:806796-HuGene_st:893171- HuGene_st ENC1216704-HuGene_st:529141-HuGene_st:968541- ENC1 1.44E−26 3.6666 3.93 96.792.6-98.7 HuGene_st:1015647-HuGene_st:524348-HuGene_st:291883-HuGene_st:154485- HuGene_st:174870-HuGene_st:967480-HuGene_st:729586-HuGene_st:826381- HuGene_st:40464-HuGene_st:340065-HuGene_st:1066975-HuGene_st:1090631-HuGene_st:201340_s_at:86039-HuGene_st:686829-HuGene_st:733896-HuGene_st:201341_at:698873-HuGene_st:730768-HuGene_st:403595-HuGene_st CD44366106-HuGene_st:314808-HuGene_st:59730- MAPK10:CD44 3.35E−26 3.71147.06 96.8 92.9-98.8 HuGene_st:599371-HuGene_st:391296-HuGene_st:1031797-HuGene_st:314340- HuGene_st:10723-HuGene_st:950067-HuGene_st:282016-HuGene_st:480680- HuGene_st:69560-HuGene_st:388781-HuGene_st:243049-HuGene_st:374652- HuGene_st:194553-HuGene_st:1075454-HuGene_st:204489_s_at:619139- HuGene_st:210916_s_at:542762-HuGene_st:1557905_s_at:212014_x_at:229221_at:204490_s_at:234418_x_at:209835_x_at:212063_at:216062_at:777408-HuGene_st:234411_x_at:217523_at: 216056_at:1565868_at:83114-HuGene_st SORD510024-HuGene_st:895709-HuGene_st:1079720- SORD 3.44E−25 3.4665 4.3695.8 91.3-98.3 HuGene_st:566899-HuGene_st:339498-HuGene_st:91263-HuGene_st:256497- HuGene_st:720484-HuGene_st:187420-HuGene_st:580807-HuGene_st:267000- HuGene_st:321981-HuGene_st:1019581-HuGene_st:1020801-HuGene_st:520376-HuGene_st:670131-HuGene_st:201562_s_at:455746-HuGene_st:67454-HuGene_st:201563_at:309303-HuGene_st:1001165-HuGene_st:411387- HuGene_st:49636-HuGene_st MYC292645-HuGene_st:257928-HuGene_st:284020- LOC731404: 5.19E−25 3.59774.11 96.4 92.2-98.6 HuGene_st:517374-HuGene_st:869576- LOC729194:HuGene_st:1099727-HuGene_st:33994- MYCHuGene_st:781657-HuGene_st:509634- HuGene_st:273419-HuGene_st:1068468-HuGene_st:1095763-HuGene_st:149150- HuGene_st:841622-HuGene_st:730300-HuGene_st:964312-HuGene_st:963427-HuGene_st:202431_s_at:522112-HuGene_st:244089_at:239931_at:649622-HuGene_st GDF15716715-HuGene_st:81268-HuGene_st:221576_at: GDF15 5.51E−25 3.5534 5.8496.2 91.9-98.5 1032661-HuGene_st:430762-HuGene_st:392223-HuGene_st:325978-HuGene_st:273598-HuGene_st:229868_s_at:835644-HuGene_st:271704-HuGene_st:1097896-HuGene_st:692830- HuGene_st:1033023-HuGene_st:85522-HuGene_st:954824-HuGene_st:221577_x_at:634293-HuGene_st:594344-HuGene_st:231517-HuGene_st:307405-HuGene_st:31827-HuGene_st:496173-HuGene_st:636515- HuGene_st:30047-HuGene_st NFE2L395873-HuGene_st:1058969-HuGene_st:86088- LOC650331: 1.51E−24 3.523 4.5796.1 91.7-98.4 HuGene_st:1093456-HuGene_st:347351- NFE2L3:HuGene_st:878719-HuGene_st:880179- 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CEL 0.0006 1.0863 1.46 70.6 61.3-78.8HuGene_st:456577-HuGene_st:1035054- HuGene_st:539061-HuGene_st:788693-HuGene_st:314198-HuGene_st:786044-HuGene_st:205910_s_at:958725-HuGene_st:473620-HuGene_st:74757-HuGene_st:169727- HuGene_st:711091-HuGene_st:461956-HuGene_st:897116-HuGene_st:911062- HuGene_st:796522-HuGene_st LILRB1213975_s_at LILRA1: 0.0013 1.0781 1.55 70.5 61.1-78.7 LILRB1 COL1A1487433-HuGene_st:719132- COL1A1 0.0018 1.0063 2.5 69.3 59.9-77.6HuGene_st:1556499_s_at:202311_s_at: 202310_s_at:1003153-HuGene_st:1029566-HuGene_st COL5A2 292241-HuGene_st COL5A2 0.0026 1.05561.36 70.1 60.8-78.3 PCSK1 981596-HuGene_st:31911-HuGene_st:701212- PCSK10.0029 1.1077 1.48 71 61.7-79.1 HuGene_st:673651-HuGene_st:166044-HuGene_st:989024-HuGene_st:1039153- HuGene_st:688811-HuGene_st:1068709-HuGene_st:1083910-HuGene_st:527047- HuGene_st:994213-HuGene_st:190818-HuGene_st:785459-HuGene_st:127562- HuGene_st:1012339-HuGene_st:343010-HuGene_st:109185-HuGene_st:115345- HuGene_st:470044-HuGene_st:856975-HuGene_st:454100-HuGene_st PCCA54827-HuGene_st:1042448-HuGene_st:175778- PCCA 0.0038 0.939 1.42 68.158.6-76.5 HuGene_st:203860_at H19634871-HuGene_st:51379-HuGene_st:803516- RPS12: 0.0051 1.0228 1.47 69.560.2-77.8 HuGene_st:336451-HuGene_st:254511- H19HuGene_st:632993-HuGene_st COL10A1 288876-HuGene_st:815716- COL10A10.0143 0.8493 2.05 66.4 56.9-74.9 HuGene_st:615071-HuGene_st:865385-HuGene_st:1067078-HuGene_st CYP3A5 NA CYP3A5: 0.0562 0.8249 1.58 6656.5-74.6 CYP3A7 CYP3A5P2 NA CYP3A5: 0.0562 0.8246 1.58 66 56.5-74.6CYP3A7 SLITRK6 NA SLITRK6 0.0576 0.8687 1.31 66.8 57.3-75.3 SPARC NASPARC 0.0684 0.6714 1.45 63.1 53.6-72   CTSE NA CTSE 0.0694 0.7465 1.8364.6  55-73.3 HOXA9 NA HOXA9 0.0759 0.7505 1.41 64.6 55.1-73.3 SFRP4 NASFRP4 0.0829 0.6983 1.29 63.7  54-72.4 COL1A2 NA COL1A2: 0.1891 0.65081.9 62.8 53.1-71.6 LOC728628 THBS2 NA THBS2 0.9844 0.2782 1.26 55.545.9-64.8

TABLE 3 Signif. Sens- TargetPS Symbol FDR D.val5 FC Spec CI (95)217523_at MAPK10:CD44 3.35E−26 3.7166 7.06 96.8 92.9-98.8 204702_s_atLOC650331:NFE2L3:LOC642996 1.51E−24 3.521 4.57 96.1 91.7-98.4 207850_atCXCL2:CXCL3 5.76E−22 3.2893 7.85 95   90-97.8 204259_at MMP7 7.61E−223.2634 69.29 94.9 89.8-97.7 228915_at DACH1 1.05E−18 2.9232 5.81 92.886.9-96.5 241031_at NLF1 3.12E−18 2.8001 8.12 91.9 85.7-95.9 223062_s_atLOC651255:PSAT1:LOC389173:LOC729779: 3.32E−15 2.4882 5.52 89.3 82.3-94.2C8orf62 206224_at CST1 7.04E−15 2.4165 13.01 88.7 81.5-93.6 209309_atAZGP1:LOC401393 1.31E−14 2.3986 6.19 88.5 81.3-93.5 219787_s_at ECT21.42E−14 2.4245 2.82 88.7 81.6-93.7 202286_s_at TACSTD2 3.13E−14 2.367615.71 88.2 80.9-93.3 227140_at No Symbol 9.19E−12 2.1522 1.61 85.978.2-91.6 229802_at No Symbol 9.19E−12 2.1536 1.61 85.9 78.2-91.6213880_at LGR5 1.10E−11 2.0621 7.89 84.9 76.9-90.8 205174_s_at QPCT3.46E−11 2.0422 3.03 84.6 76.7-90.6 238021_s_at LOC643911 3.73E−111.6459 1.33 79.5 70.8-86.5 227174_at WDR72 5.22E−11 1.9854 14.11 8475.8-90.1 238984_at REG4 5.97E−10 1.8033 7.75 81.6 73.2-88.3 204475_atMMP1 1.22E−09 1.8138 10.59 81.8 73.4-88.4 222608_s_at ANLN 4.94E−091.7541 2.63 81 72.4-87.7 211506_s_at LOC652128:IGHG1:IGHM:IGHV4-1.99E−07 1.6343 3.1 79.3 70.6-86.3 31:LOC647189:IGHV1-69:IGHA1:IL8:EXOC7:SIX6:IGHD: IGH@:IGHG3:C12orf32:ZCWPW2:IFI6:IGHG4:IGHA2:IGHG2:RAC1 204320_at COL11A1 2.93E−07 1.5718 2.6 78.469.6-85.6 37892_at COL11A1 2.93E−07 1.5707 2.6 78.4 69.6-85.6 232252_atDUSP27 4.68E−07 1.5112 4.81 77.5 68.6-84.8 225806_at C14orf94 2.40E−061.6519 1.19 79.6 70.9-86.6 204885_s_at MSLN 3.78E−06 1.4266 1.93 76.267.2-83.7 214974_x_at CXCL5 2.79E−05 1.2818 4.48 73.9 64.7-81.6236894_at L1TD1 0.0002 1.1596 2.36 71.9 62.6-79.9 205910_s_at CEL 0.00061.0869 1.46 70.7 61.3-78.8 202311_s_at COL1A1 0.0018 1.0054 2.5 69.259.9-77.6 205825_at PCSK1 0.0029 1.1086 1.48 71 61.7-79.1 226237_atCOL8A1 0.0254 0.8303 1.43 66.1 56.6-74.7 235976_at SLITRK6 0.0576 0.86891.31 66.8 57.2-75.3

TABLE 4 Gene Signif. Sens- CI Symbol ValidPS_UP Symbol FDR D.val5 FCSpec (95) CD44 366106-HuGene_st:314808-HuGene_st:59730- MAPK10:CD443.35E−26 3.7136 7.06 96.8 92.9-98.8 HuGene_st:599371-HuGene_st:391296-HuGene_st:1031797-HuGene_st:314340- HuGene_st:10723-HuGene_st:950067-HuGene_st:282016-HuGene_st:480680- HuGene_st:69560-HuGene_st:388781-HuGene_st:243049-HuGene_st:374652- HuGene_st:194553-HuGene_st:1075454-HuGene_st:204489_s_at:619139- HuGene_st:210916_s_at:542762-HuGene_st:1557905_s_at:212014_x_at:229221_at:204490_s_at:234418_x_at:209835_x_at:212063_at: 216062_at:777408-HuGene_st:234411_x_at:217523_at:216056_at: 1565868_at:83114-HuGene_stNFE2L3 95873-HuGene_st:1058969-HuGene_st:86088- LOC650331:NFE2L3:1.51E−24 3.5213 4.57 96.1 91.6-98.4 HuGene_st:1093456-HuGene_st:347351-LOC642996 HuGene_st:878719-HuGene_st:880179- HuGene_st:240089_at:822197-HuGene_st:873612-HuGene_st:517821- HuGene_st:489354-HuGene_st:20603-HuGene_st:204702_s_at MMP7 267137-HuGene_st:1068392- MMP7 7.61E−223.2652 69.29 94.9 89.8-97.8 HuGene_st:794865-HuGene_st:876922-HuGene_st:669567-HuGene_st:1039935- HuGene_st:514120-HuGene_st:1092830-HuGene_st:745768-HuGene_st:272260- HuGene_st:30733-HuGene_st:401681-HuGene_st:854024-HuGene_st:221616- HuGene_st:805045-HuGene_st:783838-HuGene_st:204259_at:934756- HuGene_st:446688-HuGene_st:10259-HuGene_st:267021-HuGene_st:889042- HuGene_st CXCL311327-HuGene_st:626337-HuGene_st:322604- CXCL2:CXCL3 1.95E−21 3.29077.85 95  90-97.8 HuGene_st:256806-HuGene_st:261067-HuGene_st:448247-HuGene_st:666569- HuGene_st:222646-HuGene_st:262117-HuGene_st:798675-HuGene_st:391369- HuGene_st:865299-HuGene_st:877897-HuGene_st:575433-HuGene_st:43120- HuGene_st:42070-HuGene_st:33632-HuGene_st:965957-HuGene_st:556939- HuGene_st:26460-HuGene_st:796450-HuGene_st:230101_at:541868- HuGene_st:490134-HuGene_st:1064107-HuGene_st:230192-HuGene_st:645829- HuGene_st:455502-HuGene_st:249140-HuGene_st:906606-HuGene_st:1098767- HuGene_st:721989-HuGene_st:500578-HuGene_st:33301- HuGene_st:207850_at:622384-HuGene_st:209774_x_at:432036- HuGene_st:30559-HuGene_st:187557-HuGene_st:1101027-HuGene_st:1038334- HuGene_st:260925-HuGene_st:515662-HuGene_st:258081- HuGene_st:1569203_at:280828-HuGene_st:1000069-HuGene_st:509822- HuGene_st:890213-HuGene_st:739461-HuGene_st:342746-HuGene_st:98929- HuGene_st:818131-HuGene_st:1091592-HuGene_st:420504-HuGene_st:41644- HuGene_st:655278-HuGene_st:188562-HuGene_st:458602-HuGene_st DACH1 686187-HuGene_st:985190- DACH1 1.05E−182.9206 5.81 92.8 86.9-96.5 HuGene_st:1011822-HuGene_st:1092705-HuGene_st:693255-HuGene_st:722787- HuGene_st:465556-HuGene_st:113230-HuGene_st:49101-HuGene_st:290879- HuGene_st:646013-HuGene_st:3984-HuGene_st:378631-HuGene_st:1002554- HuGene_st:620749-HuGene_st:802309-HuGene_st:82679- HuGene_st:205471_s_at:303920-HuGene_st:338273-HuGene_st:20454- HuGene_st:1567100_at:205472_s_at:228915_at:562342_at:169641- HuGene_st:984254-HuGene_st:1567101_at NLF1269939-HuGene_st:314919- NLF1 3.12E−18 2.8001 8.12 91.9 85.7-95.9HuGene_st:552234-HuGene_st:622058- HuGene_st:68900-HuGene_st:376228-HuGene_st:194806-HuGene_st:923707- HuGene_st:745661-HuGene_st:996995-HuGene_st:534469-HuGene_st:560627- HuGene_st:711203-HuGene_st:241031_at:93378- HuGene_st:611899-HuGene_st:57671-HuGene_st:443570-HuGene_st:231416- HuGene_st PSAT1139416-HuGene_st:795030- LOC651255:PSAT1: 3.32E−15 2.4883 5.52 89.382.3-94.1 HuGene_st:160439-HuGene_st:322148- LOC389173:LOC729779:HuGene_st:85375-HuGene_st:223335- C8orf62HuGene_st:2658-HuGene_st:399855- HuGene_st:220892_s_at:941491-HuGene_st:1017348-HuGene_st:856207- HuGene_st:194347-HuGene_st:553133-HuGene_st:223062_s_at:987517- HuGene_st:336174-HuGene_st CST195123-HuGene_st:125297-HuGene_st:235257- CST1 7.04E−15 2.4165 13.01 88.781.5-93.7 HuGene_st:102028-HuGene_st:291462- HuGene_st:206224_at:906914-HuGene_st:936009-HuGene_st:1055285- HuGene_st AZGP1363333-HuGene_st:620891- AZGP1:LOC401393 1.31E−14 2.3984 6.19 88.581.3-93.5 HuGene_st:619378-HuGene_st:741747-HuGene_st:28018-HuGene_st:594026- HuGene_st:222884-HuGene_st:1006522-HuGene_st:974237-HuGene_st:473891- HuGene_st:784628-HuGene_st:488818-HuGene_st:209309_at:217014_s_at:63620-HuGene_st:366096-HuGene_st:950952- HuGene_st:601798-HuGene_st:399823-HuGene_st:734365-HuGene_st:1054227- HuGene_st ECT2770888-HuGene_st:82454-HuGene_st:171418- ECT2 1.42E−14 2.4269 2.82 88.881.6-93.7 HuGene_st:52318-HuGene_st:530079- HuGene_st:288145-HuGene_st:234992_x_at:64803- HuGene_st:705846-HuGene_st:158755-HuGene_st:554622- HuGene_st:237241_at:629949-HuGene_st:222681-HuGene_st:241642- HuGene_st:143403-HuGene_st:770445-HuGene_st:218688-HuGene_st:700408- HuGene_st:165018-HuGene_st:917458-HuGene_st:219787_s_at:609829- HuGene_st:110350-HuGene_st TACSTD21004611-HuGene_st:755233- TACSTD2 3.13E−14 2.3693 15.71 88.2 80.9-93.3HuGene_st:815649-HuGene_st:567105- HuGene_st:8281-HuGene_st:1041491-HuGene_st:339450- HuGene_st:227128_s_at:653539-HuGene_st:1079680-HuGene_st:958592- HuGene_st:202286_s_at:620831-HuGene_st:53075-HuGene_st:1009541- HuGene_st:861600-HuGene_st:181597-HuGene_st:130895-HuGene_st:849592- HuGene_st IL81044664-HuGene_st:714746- AHNAK:IGHG1 3.28E−12 2.3273 1.73 87.8 80.3-93 HuGene_st:442029-HuGene_st:119200- HuGene_st:550444-HuGene_st:493978-HuGene_st:713906-HuGene_st:943156- HuGene_st:504843-HuGene_st:501902-HuGene_st:497219-HuGene_st:23149- HuGene_st:387164-HuGene_st:562654-HuGene_st:1047492-HuGene_st:538558- HuGene_st:239300-HuGene_st:211430_s_at:390695- HuGene_st:1081759-HuGene_st:144630-HuGene_st:661013-HuGene_st:393191- HuGene_st:55017-HuGene_st:1005159-HuGene_st:359116-HuGene_st:373132- HuGene_st:689050-HuGene_st:611041-HuGene_st:715689-HuGene_st:289354- HuGene_st:820633-HuGene_st:555788-HuGene_st:988945-HuGene_st:307991- HuGene_st:211506_s_at:924368-HuGene_st:47911-HuGene_st:929972- HuGene_st:561100-HuGene_st:68522-HuGene_st:217039_x_at:231668_x_at:1080400-HuGene_st:141662-HuGene_st:765200- HuGene_st:648539-HuGene_st:274868-HuGene_st:233969_at LGR5 784585-HuGene_st:777519- LGR5 1.10E−11 2.06457.89 84.9 76.9-90.8 HuGene_st:937559-HuGene_st:297045-HuGene_st:796093-HuGene_st:783411- HuGene_st:876648-HuGene_st:842003-HuGene_st:102017-HuGene_st:562251- HuGene_st:295997-HuGene_st:747520-HuGene_st:811121-HuGene_st:677407- HuGene_st:522834-HuGene_st:475414-HuGene_st:802999-HuGene_st:1066925- HuGene_st:216864-HuGene_st:890928-HuGene_st:179502-HuGene_st:79633-HuGene_st:210393_at:241266_at:213880_at QPCT 261837-HuGene_st:108729-QPCT 3.46E−11 2.0415 3.03 84.6 76.7-90.6HuGene_st:942514-HuGene_st:184578- HuGene_st:454020-HuGene_st:202482-HuGene_st:1012784-HuGene_st:854999- HuGene_st:62841-HuGene_st:271540-HuGene_st:524919-HuGene_st:78507- HuGene_st:89785-HuGene_st:728309-HuGene_st:625205-HuGene_st:170279- HuGene_st:561083-HuGene_st:322236-HuGene_st:205174_s_at:303448-HuGene_st WDR72 829740-HuGene_st:1063796-WDR72 5.22E−11 1.9856 14.11 84 75.9-90  HuGene_st:725768-HuGene_st:227174_at:36564- HuGene_st:236741_at:604794-HuGene_st:1040675-HuGene_st:527199- HuGene_st:1052168-HuGene_st:1563874_at:177868- HuGene_st:667158-HuGene_st:542462-HuGene_st:136243-HuGene_st:551835- HuGene_st REG4186424-HuGene_st:382639- REG4 5.97E−10 1.8057 7.75 81.7 73.3-88.3HuGene_st:931162-HuGene_st:400261- HuGene_st:638045-HuGene_st:852602-HuGene_st:628254-HuGene_st:849775- HuGene_st:274371-HuGene_st:1554436_a_at:1092015- HuGene_st:223447_at:29614-HuGene_st:661518-HuGene_st:580789- HuGene_st:929866-HuGene_st:160171-HuGene_st:954850-HuGene_st:758344- HuGene_st:254891-HuGene_st:238984_at:421464- HuGene_st:758547-HuGene_st:364821-HuGene_st:701510-HuGene_st MMP1 61706-HuGene_st:300572- MMP1 1.22E−091.8141 10.59 81.8 73.4-88.4 HuGene_st:1020786-HuGene_st:437171-HuGene_st:671620-HuGene_st:689073 - HuGene_st:622653-HuGene_st:958445-HuGene_st:445730-HuGene_st:914223- HuGene_st:693724-HuGene_st:673683-HuGene_st:524115-HuGene_st:422476- HuGene_st:361198-HuGene_st:710307-HuGene_st:468477-HuGene_st:840324- HuGene_st:1070117-HuGene_st:473664-HuGene_st:732367- HuGene_st:204475_at:353235-HuGene_st ANLN522941-HuGene_st:550252- ANLN 4.94E−09 1.7566 2.63 81 72.5-87.7HuGene_st:477118-HuGene_st:858635- HuGene_st:34728-HuGene_st:165560-HuGene_st:226318-HuGene_st:207100- HuGene_st:842538-HuGene_st:343961-HuGene_st:899690-HuGene_st:705871- HuGene_st:42619-HuGene_st:984996-HuGene_st:733290-HuGene_st:1008901- HuGene_st:752472-HuGene_st:619756-HuGene_st:674545-HuGene_st:558324- HuGene_st:261208-HuGene_st:222608_s_at:1552619_a_at COL11A1 254341-HuGene_st:485975-COL11A1 2.93E−07 1.5724 2.6 78.4 69.6-85.6HuGene_st:869898-HuGene_st:755872- HuGene_st:2674-HuGene_st:230890-HuGene_st:6042-HuGene_st:1100922- HuGene_st:800510-HuGene_st:64257-HuGene_st:301971-HuGene_st:360139- HuGene_st:549979-HuGene_st:603002-HuGene_st:756718-HuGene_st:1043994- HuGene_st:198973-HuGene_st:550144-HuGene_st:986684-HuGene_st:743059- HuGene_st:708360-HuGene_st:575064-HuGene_st:633985-HuGene_st:392228- HuGene_st:204320_at:121425-HuGene_st:468885-HuGene_st:20543- HuGene_st:170503-HuGene_st DUSP27612025-HuGene_st:737703- DUSP27 4.68E−07 1.5098 4.81 77.5 68.6-84.8HuGene_st:124098-HuGene_st:102948- HuGene_st:35826-HuGene_st:226732-HuGene_st:513585-HuGene_st:135885- HuGene_st:737040-HuGene_st:446627-HuGene_st:724445-HuGene_st:289189- HuGene_st:5396-HuGene_st:520095-HuGene_st:172210-HuGene_st:277848- HuGene_st:312172-HuGene_st:903613-HuGene_st:232252_at:303717- HuGene_st:846174-HuGene_st C14orf94225806_at:243446_at:88782- C14orf94 2.40E−06 1.6524 1.19 79.6 70.9-86.5HuGene_st:537586-HuGene_st:973643- HuGene_st:646464-HuGene_st:729584-HuGene_st:973338-HuGene_st:95576- HuGene_st:301260-HuGene_st:559586-HuGene_st:942952-HuGene_st:82798- HuGene_st:218383_at:165751-HuGene_st:965936-HuGene_st:31043- HuGene_st:650638-HuGene_st:984201-HuGene_st:925802-HuGene_st:306659- HuGene_st:345230-HuGene_st MSLN63302-HuGene_st:821643-HuGene_st:99135- MSLN 3.78E−06 1.427 1.93 76.267.2-83.7 HuGene_st:192667-HuGene_st:765000-HuGene_st:44188-HuGene_st:59621- HuGene_st:465236-HuGene_st:559922-HuGene_st:82252-HuGene_st:1039687- HuGene_st:1053735- HuGene_st:204885_s_at:870302- HuGene_st:246473-HuGene_st:58043-HuGene_st:122629-HuGene_st:826602- HuGene_st:689741-HuGene_st:931732-HuGene_st:227498-HuGene_st CXCL5 264137-HuGene_st:272626- CXCL5 2.79E−051.2814 4.48 73.9 64.7-81.7 HuGene_st:745715-HuGene_st:968572-HuGene_st:1054472-HuGene_st:394185- HuGene_st:181128-HuGene_st:456756-HuGene_st:415578- HuGene_st:215101_s_at:214974_x_at:935926-HuGene_st:781518-HuGene_st:235326- HuGene_st:941963-HuGene_st:242589-HuGene_st:798477-HuGene_st:257906- HuGene_st:350119-HuGene_st:222708-HuGene_st L1TD1 859419-HuGene_st:968483- L1TD1 2.00E−04 1.1595 2.36 71.962.6-79.9 HuGene_st:1010927- HuGene_st:236894_at:715579-HuGene_st:540230-HuGene_st:414266- HuGene_st:572495-HuGene_st:327643-HuGene_st:1058922-HuGene_st:18534- HuGene_st:1063550-HuGene_st:1030986-HuGene_st:842123-HuGene_st:709222- HuGene_st:887612-HuGene_st:219955_at:496121- HuGene_st:942986-HuGene_st:799837- HuGene_stCEL 1553970_s_at:898561-HuGene_st:857424- CEL 6.00E−04 1.0872 1.46 70.761.3-78.8 HuGene_st:456577-HuGene_st:1035054-HuGene_st:539061-HuGene_st:788693- HuGene_st:314198-HuGene_st:786044-HuGene_st:205910_s_at:958725- HuGene_st:473620-HuGene_st:74757-HuGene_st:169727-HuGene_st:711091- HuGene_st:461956-HuGene_st:897116-HuGene_st:911062-HuGene_st:796522- HuGene_st COL1A1487433-HuGene_st:719132- COL1A1 1.80E−03 1.0053 2.5 69.2 59.9-77.6HuGene_st:1556499_s_at:202311_s_at: 202310_s_at:1003153-HuGene_st:1029566-HuGene_st PCSK1981596-HuGene_st:31911-HuGene_st:701212- PCSK1 2.90E−03 1.1082 1.48 7161.6-79.1 HuGene_st:673651-HuGene_st:166044-HuGene_st:989024-HuGene_st:1039153- HuGene_st:688811-HuGene_st:1068709-HuGene_st:1083910-HuGene_st:527047- HuGene_st:994213-HuGene_st:190818-HuGene_st:785459-HuGene_st:127562- HuGene_st:1012339-HuGene_st:343010-HuGene_st:109185-HuGene_st:115345- HuGene_st:470044-HuGene_st:85 6975-HuGene_st:454100-HuGene_st COL8A1 713455-HuGene_st COL8A1 2.54E−020.8325 1.43 66.1 56.6-74.7

TABLE 5 Signif. Sens- CI TargetPS Symbol FDR D.val5 FC Spec (95)213106_at ATP8A1 6.60E−08 2.2884 3.11 87.4 76.9-94.1 210107_at CLCA13.19E−07 2.1573 9.98 86 75.2-93.1 204811_s_at CACNA2D2 3.61E−05 1.6594.41 79.7 67.7-88.5 223969_s_at RETNLB 4.3968E−05  1.6581 11.64 79.667.7-88.5 223970_at RETNLB 4.3968E−05  1.6576 11.64 79.6 67.8-88.5228232_s_at VSIG2 0.0001 1.5718 2.4 78.4 66.3-87.6 242601_at LOC2530120.0001 1.5777 5.28 78.5 66.5-87.6 227719_at No Symbol 0.0002 1.642 1.9879.4 67.4-88.3 237521_x_at No Symbol 0.0002 1.6433 1.98 79.4 67.5-88.3203240_at FCGBP 3.00E−04 1.5005 3.07 77.3 65.2-86.7 204897_at PTGER46.00E−04 1.4732 1.55 76.9 64.7-86.4 227676_at FAM3D 0.001  1.2706 2.1573.7 61.3-83.8 205765_at CYP3A5 1.20E−03 1.5279 1.8 77.8 65.6-87.1232176_at SLITRK6 0.0016 1.3618 5.96 75.2 62.8-85  232481_s_at SLITRK60.0016 1.3607 5.96 75.2 62.9-85  235976_at SLITRK6 0.0016 1.3648 5.9675.3 62.9-84.9 221874_at KIAA1324 3.80E−03 1.325 2.1 74.6 62.2-84.5226248_s_at KIAA1324 0.0038 1.3246 2.1 74.6 62.2-84.6 204607_at HMGCS25.20E−03 1.2354 3.59 73.2 60.7-83.3 203963_at CA12 6.50E−03 1.1828 1.8672.3 59.7-82.6 204508_s_at CA12 6.50E−03 1.1861 1.86 72.3 59.8-82.6215867_x_at CA12 6.50E−03 1.1858 1.86 72.3 59.7-82.6 227725_atST6GALNAC1 0.0068 1.1419 1.76 71.6 59-82 200884_at CKB 7.30E−03 1.14812.25 71.7 59.1-82.1 219955_at L1TD1 7.70E−03 1.2502 3.27 73.4 60.9-83.5236894_at L1TD1 0.0077 1.2465 3.27 73.3 60.9-83.5 205259_at NR3C21.29E−02 1.1933 1.63 72.5 60.1-82.8 218211_s_at MLPH 1.38E−02 1.22691.59 73 60.5-83.2 214234_s_at CYP3A5P2 1.94E−02 1.098 1.7 70.8 58.1-81.3214235_at CYP3A5P2 1.94E−02 1.0976 1.7 70.8 58.2-81.3 204895_x_atMUC4:TAF5L:LOC650855:LOC645744 4.53E−02 1.1998 1.31 72.6 60.1-82.8217109_at MUC4:TAF5L:LOC650855:LOC645744 4.53E−02 1.2028 1.31 72.660.2-82.8 217110_s_at MUC4:TAF5L:LOC650855:LOC645744 4.53E−02 1.198 1.3172.5  60-82.8 221841_s_at KLF4 7.31E−02 1.0009 1.58 69.2 56.5-79.9215125_s_at UGT1A9 7.37E−02 1.0664 1.28 70.3 57.6-80.9 208063_s_at CAPN97.40E−02 0.998 1.84 69.1 56.4-79.9 214433_s_at SELENBP1 9.02E−02 0.97832 68.8  56-79.6 226302_at ATP8B1 0.093  1.039 1.4 69.8 57.2-80.5231832_at WDR51B 0.1284 1.0008 1.28 69.2 56.5-79.9 219543_at PBLD1.66E−01 0.8734 1.89 66.9 54.2-77.9 208937_s_at ID1 2.34E−01 0.7639 1.6664.9 52.1-76.2 205927_s_at CTSE 2.81E−01 0.7393 3.23 64.4 51.6-75.8229070_at C6orf105 0.7794 0.7027 1.37 63.7 50.9-75.2

TABLE 6 Signif. Sens- CI TargetPS Symbol FDR D.val5 FC Spec (95)200665_s_at SPARC  3.05E−09 2.3771 3.24 88.3  78-94.6 212667_at SPARC3.0479E−09 2.3752 3.24 88.3 78.1-94.6 211964_at COL4A2 5.5315E−09 2.43162.87 88.8 78.8-95  211966_at COL4A2 5.5315E−09 2.4321 2.87 88.8 78.8-95 211980_at COL4A1  1.243E−08 2.3031 3.03 87.5 77.2-94.2 211981_at COL4A1 1.243E−08 2.3045 3.03 87.5 77.2-94.2 218638_s_at SPON2 1.9471E−082.3321 3.38 87.8 77.5-94.3 221729_at COL5A2 5.7658E−08 2.2145 3.31 86.6 76-93.5 221730_at COL5A2 5.7658E−08 2.2138 3.31 86.6 75.9-93.6208782_at FSTL1 7.8434E−08 2.228 2.64 86.7 76.1-93.7 201261_x_at BGN9.6881E−08 2.2253 2.99 86.7  76-93.6 213905_x_at BGN 9.6881E−08 2.22322.99 86.7 76.1-93.6 209955_s_at IFIH1:FAP  1.358E−07 2.2261 4.88 86.776.2-93.6 226237_at COL8A1 3.6053E−07 2.1456 3.09 85.8 75-93 202310_s_atCOL1A1  5.44E−07 2.012 3.29 84.3 73-92 202311_s_at COL1A1  5.44E−072.0131 3.29 84.3 73.1-92  217430_x_at COL1A1 5.4426E−07 2.015 3.29 84.373.2-92  201438_at COL6A3 5.7026E−07 2.0286 2.73 84.5 73.5-92.1202403_s_at COL1A2:LOC728628  8.85E−07 2.0609 2.62 84.9 73.9-92.4202404_s_at COL1A2:LOC728628  8.85E−07 2.0621 2.62 84.9 73.7-92.4229218_at COL1A2:LOC728628 8.8466E−07 2.0618 2.62 84.9 73.9-92.4208850_s_at THY1 1.0326E−06 1.9159 3.34 83.1 71.8-91.1 208851_s_at THY11.0326E−06 1.915 3.34 83.1 71.7-91.1 213869_x_at THY1 1.0326E−06 1.91323.34 83.1 71.7-91.1 203477_at COL15A1 1.0611E−06 2.0121 3.37 84.373.2-91.9 201616_s_at CALD1  1.11E−06 2.1136 1.7 85.5 74.6-92.8212077_at CALD1 1.1059E−06 2.1131 1.7 85.5 74.5-92.8 201162_at IGFBP71.1574E−06 2.0016 1.91 84.2 72.9-91.8 201163_s_at IGFBP7  1.16E−06 1.9991.91 84.1  73-91.9 210511_s_at INHBA 1.1943E−06 2.0027 3.38 84.2 73-91.9 225664_at TMEM30A:COL12A1 1.2492E−06 2.0313 4.16 84.5 73.4-92.1231766_s_at TMEM30A:COL12A1 1.2492E−06 2.0303 4.16 84.5 73.4-92.1231879_at TMEM30A:COL12A1 1.2492E−06 2.0325 4.16 84.5 73.5-92.1203325_s_at COL5A1 1.6076E−06 1.934 2.75 83.3 72.1-91.3 212488_at COL5A11.6076E−06 1.9342 2.75 83.3 72.1-91.3 212489_at COL5A1 1.6076E−06 1.93392.75 83.3  72-91.2 203083_at THBS2 2.3382E−06 1.9081 6.5 83 71.6-91 202291_s _at MGP:C12orf46  2.50E−06 1.999 2.62 84.1  73-91.9 201645_atTNC  3.74E−06 1.9608 2.14 83.7 72.5-91.5 201852_x_at COL3A1  9.29E−061.8472 2.32 82.2 70.7-90.5 211161_s_at COL3A1 9.2906E−06 1.8501 2.3282.3 70.7-90.5 215076_s_at COL3A1 9.2906E−06 1.8495 2.32 82.2 70.7-90.5232458_at COL3A1 9.2906E−06 1.8473 2.32 82.2 70.7-90.5 212344_at SULF11.4436E−05 1.7528 2.84 81 69.3-89.5 212353_at SULF1 1.4436E−05 1.75552.84 81 69.2-89.5 212354_at SULF1 1.4436E−05 1.7521 2.84 80.9 69.3-89.5201185_at HTRA1 1.7178E−05 1.7346 2.29 80.7 68.9-89.3 202998_s_atENTPD4:LOXL2  1.99E−05 1.7754 2.45 81.3 69.6-89.7 224724_at SULF22.0766E−05 1.6837 2.25 80 68.2-88.7 233555_s_at SULF2 2.0766E−05 1.67952.25 79.9  68-88.7 201069_at MMP2 2.5409E−05 1.7345 3.02 80.7  69-89.3201147_s_at TIMP3  2.62E−05 1.7776 2.56 81.3 69.6-89.7 201150_s_at TIMP3 2.62E−05 1.7774 2.56 81.3 69.6-89.7 209156_s_at COL6A2 2.9551E−051.7373 1.67 80.7  69-89.4 227099_s_at LOC387763   0.00003052 1.8968 1.4382.9 71.4-90.9 214247_s_at DKK3 3.1838E−05 1.7434 1.86 80.8 69.1-89.5202450_s_at CTSK  3.98E−05 1.7153 2.16 80.4 68.7-89.1 225799_at MGC4677,MGC4677:LOC541471 4.1139E−05 1.8003 1.45 81.6 70-90 209395_atCHI3L1:MYBPH 5.1515E−05 1.6358 3.06 79.3 67.4-88.2 209396_s_atCHI3L1:MYBPH 5.1515E−05 1.6352 3.06 79.3 67.4-88.2 202878_ s_at CD93 5.19E−05 1.667 2.36 79.8 67.9-88.6 204320_at COL11A1 5.3391E−05 1.75942.55 81 69.3-89.6 37892_at COL11A1 5.3391E−05 1.7556 2.55 81 69.3-89.6221011_s_at LBH 6.3299E−05 1.6771 1.9 79.9 68.1-88.7 213125_at OLFML2B6.6557E−05 1.7057 1.97 80.3 68.5-89  204475_at MMP1 7.0616E−05 1.67593.91 79.9  68-88.8 226694_at AKAP2:PALM2:PALM2-AKAP2 7.4206E−05 1.72311.58 80.6 68.8-89.2 202766_s_at FBN1 0.0001 1.5984 1.48 78.8 66.7-87.9205828_at MMP3 0.0001 1.6223 6.68 79.1 67.3-88.1 207191_s_at ISLR 0.00011.6448 1.87 79.5 67.5-88.4 213428_s_at COL6A1 0.0001 1.7301 1.58 80.668.8-89.3 226930_at FNDC1 0.0001 1.521 3.14 77.7 65.6-87  201792_atAEBP1 0.0002 1.4772 2.11 77 64.8-86.5 203878_s_at MMP11 0.0002 1.69711.28 80.2 68.4-88.9 211959_at IGFBP5 0.0002 1.5662 3.96 78.3 66.3-87.5225710_at No Symbol 0.0002 1.6426 1.98 79.4 67.5-88.4 226311_at NoSymbol 0.0002 1.6436 1.98 79.4 67.5-88.3 226777_at No Symbol 0.00021.645 1.98 79.5 67.5-88.4 227140_at No Symbol 0.0002 1.6427 1.98 79.467.6-88.3 229802_at No Symbol 0.0002 1.6421 1.98 79.4 67.5-88.3205479_s_at PLAU 0.0003 1.484 2.11 77.1 64.9-86.5 210495_x_at FN1 0.00031.494 2.87 77.2 65.1-86.6 211719_x_at FN1 0.0003 1.4894 2.87 77.265.1-86.7 212464_s_at FN1 0.0003 1.493 2.87 77.2  65-86.7 216442_x_atFN1 0.0003 1.4935 2.87 77.2  65-86.6 217762_s_at RAB31 0.0003 1.48642.08 77.1  65-86.6 217763_s_at RAB31 0.0003 1.4848 2.08 77.1 64.9-86.6217764_s_at RAB31 0.0003 1.4882 2.08 77.2  65-86.5 225681_at CTHRC10.0003 1.4588 3.41 76.7 64.5-86.3 201105_at LGALS1 0.0004 1.4844 1.6177.1 64.9-86.6 208788_at ELOVL5 0.0004 1.5418 1.86 78 65.8-87.2224694_at ANTXR1 0.0005 1.52 2 77.6 65.5-86.9 200974_at ACTA2 0.00061.4251 1.75 76.2  64-85.8 210095_s_at IGFBP3 0.0006 1.5538 1.38 78.1 66-87.4 201426_s_at VIM  8.00E−04 1.4819 1.48 77.1 64.9-86.4 219087_atASPN 0.0009 1.4046 2.75 75.9 63.6-85.5 227566_at HNT 0.001  1.4215 2.2676.1  64-85.7 201667_at GJA1  1.30E−03 1.4084 1.63 75.9 63.7-85.6200600_at MSN  1.40E−03 1.4942 1.36 77.2  65-86.7 204051_s_at SFRP40.0015 1.4056 2.2 75.9 63.6-85.6 209101_at CTGF 0.0015 1.3331 1.78 74.762.4-84.6 204620_s_at CSPG2 0.0016 1.21 1.38 72.7 60.3-83  211571_s_atCSPG2 0.0016 1.2123 1.38 72.8 60.1-82.9 215646_s_at CSPG2 0.0016 1.20951.38 72.7 60.3-83  221731_x_at CSPG2 0.0016 1.2115 1.38 72.8 60.3-83 204006_s_at FCGR3B 0.0026 1.2308 2.14 73.1 60.6-83.2 203570_at LOXL10.0027 1.4048 1.33 75.9 63.7-85.6 201744_s_at LUM  2.90E−03 1.3418 2.1874.9 62.5-84.7 202283_at SERPINF1  3.10E−03 1.2121 1.76 72.8 60.2-83 209596_at MXRA5 0.0034 1.2974 1.62 74.2 61.7-84.1 210809_s_at POSTN0.005  1.3011 2.58 74.2 61.8-84.2 205547_s_at TAGLN 0.0051 1.1829 2.1972.3 59.7-82.6 202237_at NNMT  5.40E−03 1.223 1.44 73 60.4-83.1202238_s_at NNMT  5.40E−03 1.2259 1.44 73 60.5-83.1 218468_s_at GREM10.007  1.3017 1.31 74.2 61.8-84.2 218469_at GREM1 0.007  1.3027 1.3174.3 61.9-84.2 208747_s_at C1S 0.0088 1.3575 1.77 75.1 62.9-85 224560_at TIMP2 0.0097 1.1629 1.72 72 59.4-82.3 231579_s_at TIMP2 0.00971.1641 1.72 72 59.5-82.4 209875_s_at SPP1 0.0109 1.0673 3.91 70.357.6-80.9 202859_x_at IL8 0.0112 1.3238 4.54 74.6 62.2-84.5 200832_s_atSCD:LOC651109:LOC645313  1.27E−02 1.0749 2.33 70.5 57.9-81.1 201058_s_atMYL9 0.0131 1.1765 1.37 72.2 59.6-82.5 203645_s_at CD163 0.0146 1.16552.19 72 59.4-82.3 215049_x_at CD163 0.0146 1.1664 2.19 72 59.4-82.3202917_s_at S100A8  1.48E−02 1.0979 3.17 70.8 58.3-81.4 201289_at CYR610.015  1.0919 1.69 70.7 58.1-81.2 210764_s_at CYR61 0.015  1.0938 1.6970.8 58.2-81.2 218559_s_at MAFB 0.0182 1.162 1.48 71.9 59.3-82.3203382_s_at APOE 0.0285 1.1124 1.43 71.1 58.5-81.6 201893_x_at DCN 3.64E−02 1.0821 1.29 70.6  58-81.1 211813_x_at DCN 0.0364 1.083 1.2970.6 57.8-81.1 211896_s_at DCN 0.0364 1.0814 1.29 70.6  58-81.1213524_s_at G0S2 0.0383 0.994 1.53 69 56.3-79.8 207173_x_at CDH11 0.03841.0121 1.98 69.4 56.6-80.1 209218_at SQLE 0.041  1.0162 2.15 69.456.6-80.1 201141_at GPNMB 0.0623 1.0165 1.52 69.4 56.7-80.1 201859_atPRG1 0.0634 0.798 1.34 65.5 52.6-76.7 234994_at KIAA1913 0.1061 0.95791.2 68.4 55.7-79.3 223122_s_at SFRP2 0.1336 0.968 1.24 68.6 55.9-79.4223235_s_at SMOC2 0.2175 0.6547 2.06 62.8  50-74.4 200986_at SERPING10.2636 0.7831 1.26 65.2 52.4-76.4 201842_s_at EFEMP1  4.91E−01 0.68211.27 63.3 50.5-74.8 204122_at TYROBP 0.4923 0.7066 1.23 63.8 51.1-75.3202620_s_at PLOD2  5.15E−01 0.7784 1.51 65.1 52.3-76.4

TABLE 7 Gene Signif. Sens- CI Symbol ValidPS_UP Symbol FDR D.val5 FCSpec (95) ATP8A1 231484_at:792569- ATP8A1 6.60E−08 2.2854 3.11 87.376.9-94  HuGene_st:210192_at:393806- HuGene_st:743026-HuGene_st:200684-HuGene_st:1570592_a_at:645563- HuGene_st:245580-HuGene_st:175799-HuGene_st:20566-HuGene_st:636204- HuGene_st:376757-HuGene_st:273140-HuGene_st:873028-HuGene_st:864954- HuGene_st:349056-HuGene_st:538894-HuGene_st:167620-HuGene_st:807498- HuGene_st CLCA1210107_at:426361-HuGene_st:389155- CLCA1 3.19E−07 2.1536 9.98 85.975.1-93.1 HuGene_st:622359-HuGene_st:523802-HuGene_st:196470-HuGene_st:1078884- HuGene_st:515258-HuGene_st:638133-HuGene_st:764167-HuGene_st:921948- HuGene_st:372283-HuGene_st:252084-HuGene_st:98798-HuGene_st:1059095- HuGene_st:441678-HuGene_st:490107-HuGene_st:284008-HuGene_st:258568- HuGene_st:602588-HuGene_st:472452-HuGene_st:640066-HuGene_st CACNA2D2 805306-HuGene_st:1022165- CACNA2D23.61E−05 1.6587 4.41 79.7 67.8-88.5 HuGene_st:356782-HuGene_st:70395-HuGene_st:525161-HuGene_st:729314- HuGene_st:866616-HuGene_st:13978-HuGene_st:715678-HuGene_st:299289- HuGene_st:592015-HuGene_st:756393-HuGene_st:607464-HuGene_st:862691- HuGene_st:229636_at:885048-HuGene_st:680228-HuGene_st:393608- HuGene_st:886897-HuGene_st:413699-HuGene_st RETNLB 173654-HuGene_st:223970_at:1094109- RETNLB 4.40E−051.6599 11.64 79.7 67.8-88.5 HuGene_st:708431-HuGene_st:231770-HuGene_st:1065075-HuGene_st:318917- HuGene_st:719419-HuGene_st:380366-HuGene_st:221119-HuGene_st:774168- HuGene_st:223969_s_at:523432-HuGene_st:45260-HuGene_st:963420- HuGene_st:329703-HuGene_st:223761-HuGene_st:1036667-HuGene_st:143113- HuGene_st:414008-HuGene_st:232543-HuGene_st VSIG2 391438-HuGene_st:228232_s_at:265221- VSIG2 0.0001 1.57452.4 78.4 66.3-87.6 HuGene_st:343187-HuGene_st:223925-HuGene_st:652010-HuGene_st:1069591- HuGene_st:265186-HuGene_st:1095607-HuGene_st:788466-HuGene_st:675062- HuGene_st:826720-HuGene_st:1093892-HuGene_st:985113-HuGene_st:637781- HuGene_st:997596-HuGene_st LOC2530121014415-HuGene_st:912640- LOC253012 0.0001 1.5764 5.28 78.5 66.5-87.7HuGene_st:463072-HuGene_st:749900- HuGene_st:381523-HuGene_st:896826-HuGene_st:804632-HuGene_st:304834- HuGene_st:39629-HuGene_st:568837-HuGene_st:1070854-HuGene_st:162938- HuGene_st:1026726-HuGene_st:441915-HuGene_st:242601_at:51876- HuGene_st:199784-HuGene_st:363568-HuGene_st:50979-HuGene_st:736612- HuGene_st FCGBP203240_at:88809-HuGene_st:1085208- FCGBP 0.0003 1.4997 3.07 77.365.2-86.7 HuGene_st:338164-HuGene_st:71797-HuGene_st:1079875-HuGene_st:63672- HuGene_st:997435-HuGene_st:226428-HuGene_st:948120-HuGene_st:22847- HuGene_st:36995-HuGene_st:508230-HuGene_st:16108-HuGene_st:311904- HuGene_st:426005-HuGene_st:27264-HuGene_st:516715-HuGene_st:841000- HuGene_st:708701-HuGene_st:781083-HuGene_st:634071-HuGene_st:948682- HuGene_st PTGER4204896_s_at:109314-HuGene_st:986807- PTGER4 0.0006 1.4713 1.55 76.964.7-86.4 HuGene_st:446764-HuGene_st:548266-HuGene_st:919403-HuGene_st:965220- HuGene_st:192344-HuGene_st:1943-HuGene_st:252442-HuGene_st:392964- HuGene_st:23686-HuGene_st:204897_at:812085-HuGene_st FAM3D 361373-HuGene_st:963526-FAM3D 0.001 1.2699 2.15 73.7 61.3-83.8 HuGene_st:227676_at:741172-HuGene_st:608385-HuGene_st:1074915- HuGene_st:182670-HuGene_st:24363-HuGene_st:269456-HuGene_st:833883- HuGene_st:280625-HuGene_st:187246-HuGene_st:964986-HuGene_st:66738- HuGene_st:80884-HuGene_st CYP3A5205765_at:67735- CYP3A5 0.0012 1.5288 1.8 77.8 65.7-87 HuGene_st:214234_s_at:941416- HuGene_st:238807-HuGene_st:611620-HuGene_st CYP3A5P2 205765_at:67735- CYP3A5 0.0012 1.5297 1.8 77.865.6-87  HuGene_st:214234_s_at:941416-HuGene_st:238807-HuGene_st:611620- HuGene_st SLITRK6936650-HuGene_st:921047- SLITRK6 0.0016 1.36 5.96 75.2 62.8-85 HuGene_st:371185-HuGene_st:510939- HuGene_st:356154-HuGene_st:205559-HuGene_st:386297-HuGene_st:483895- HuGene_st:227644-HuGene_st:458058-HuGene_st:232481_s_at:907326- HuGene_st:255645-HuGene_st:830582-HuGene_st:615220-HuGene_st:369624- HuGene_st:78770-HuGene_st:573187-HuGene_st:1025122-HuGene_st:584646- HuGene_st KIAA1324243349_at:226248_s_at:1052694- KIAA1324 0.0038 1.3258 2.1 74.6 62.2-84.5HuGene_st:893707-HuGene_st:597814- HuGene_st:585604-HuGene_st:240530-HuGene_st HMGCS2 616916-HuGene_st:283650- HMGCS2 0.0052 1.234 3.59 73.160.6-83.3 HuGene_st:204607_at:43162- HuGene_st:371076-HuGene_st:407398-HuGene_st:900260-HuGene_st:619083- HuGene_st:729816-HuGene_st:171889-HuGene_st:253113-HuGene_st:448587- HuGene_st:593619-HuGene_st:624250-HuGene_st:865416-HuGene_st:888308- HuGene_st:397691-HuGene_st:789982-HuGene_st:658722-HuGene_st CA12 215867_x_at:210735_s_at:204508_s_at:CA12 0.0065 1.1823 1.86 72.3 59.7-82.6 203963_at:638145-HuGene_st:1013062-HuGene_st:280470- HuGene_st:214164_x_at:875965-HuGene_st:749017-HuGene_st:1049334- HuGene_st:439438-HuGene_st:65565-HuGene_st:1017708-HuGene_st:226479- HuGene_st:125567-HuGene_st:698714-HuGene_st:963408-HuGene_st:189118- HuGene_st:1049350-HuGene_stST6GALNAC1 524915-HuGene_st:694442- ST6GALNAC1 0.0068 1.1407 1.76 71.658.9-82  HuGene_st:372293-HuGene_st:247017-HuGene_st:186959-HuGene_st:149798- HuGene_st:611157-HuGene_st:887450-HuGene_st:227725_at:608767- HuGene_st:891399-HuGene_st:95718-HuGene_st:780611-HuGene_st:1006431- HuGene_st:266448-HuGene_st:768462-HuGene_st:616368-HuGene_st:66760- HuGene_st:1067993-HuGene_st:69927-HuGene_st:104705-HuGene_st CKB 200884_at:435665-HuGene_st:888623- CKB0.0073 1.1468 2.25 71.7 59.2-82.1 HuGene_st:480007-HuGene_st:396007-HuGene_st:963331-HuGene_st:40899- HuGene_st:373774-HuGene_st:25470-HuGene_st:16603-HuGene_st:766369- HuGene_st:405417-HuGene_st:718720-HuGene_st:1041238-HuGene_st:23457- HuGene_st:24890-HuGene_st:769422-HuGene_st:896708-HuGene_st:581051- HuGene_st:549987-HuGene_st:384128-HuGene_st L1TD1 219955_at:842123-HuGene_st:1095330- L1TD1 0.0077 1.24973.27 73.4 60.9-83.5 HuGene_st:1058922-HuGene_st:572495-HuGene_st:414266-HuGene_st:887612- HuGene_st:799837-HuGene_st:177635-HuGene_st:715579-HuGene_st:709222- HuGene_st:968483-HuGene_st:1030986-HuGene_st:327643-HuGene_st:540230- HuGene_st NR3C2100953-HuGene_st:239673_at:981978- NR3C2 0.0129 1.1951 1.63 72.559.9-82.7 HuGene_st MLPH 218211_s_at MLPH 0.0138 1.2275 1.59 7360.5-83.2 UGT1A1 208596_s_at:221305_s_at:204532_x_at: UGT1A3 0.03761.0578 1.68 70.2 57.5-80.8 232654_s_at MUC4 NA MUC4:TAF5L:LOC650855:0.0453 1.1986 1.31 72.6 60.1-82.8 LOC645744 KLF4 NA KLF4 0.0731 1.00181.58 69.2 56.5-79.9 CAPN9 NA CAPN9 0.074 0.9979 1.84 69.1 56.4-79.9SELENBP1 NA SELENBP1 0.0902 0.9777 2 68.8 56.1-79.6 ATP8B1 NA ATP8B10.093 1.0347 1.4 69.8 57.2-80.4 WDR51B NA WDR51B 0.1284 1.0004 1.28 69.256.5-80  PBLD NA PBLD 0.1655 0.8731 1.89 66.9 54.1-78  ID1 NA ID1 0.23420.7662 1.66 64.9 52.2-76.2 CTSE NA CTSE 0.2809 0.7409 3.23 64.451.7-75.8 C6orf105 NA C6orf105 0.7794 0.7003 1.37 63.7 50.8-75.1

TABLE 8 Gene Signif. Sens- CI Symbol ValidPS_UP Symbol FDR D.val5 FCSpec (95) SPARC 677215-HuGene_st:456544- SPARC 3.0479E−09 2.3799 3.2488.3 78.1-94.6 HuGene_st:1041514-HuGene_st:868223-HuGene_st:1053181-HuGene_st:196416- HuGene_st:1078055-HuGene_st:213861-HuGene_st:452422-HuGene_st:1078242- HuGene_st:497056-HuGene_st:1285-HuGene_st:793848-HuGene_st:455765- HuGene_st:72235-HuGene_st:568912-HuGene_st:887159-HuGene_st:255885- HuGene_st:225477-HuGene_st:162094-HuGene_st:1026630- HuGene_st:200665_s_at COL4A2 540082-HuGene_st:295949-COL4A2 5.5315E−09 2.4297 2.87 88.8 78.6-95 HuGene_st:1009411-HuGene_st:245530- HuGene_st:834880-HuGene_st:801333-HuGene_st:500428-HuGene_st:990355- HuGene_st:469754-HuGene_st:980150-HuGene_st:184258-HuGene_st:580118- HuGene_st:281233-HuGene_st:732269-HuGene_st:1075712-HuGene_st:643598- HuGene_st:772366-HuGene_st:211966_at:512520- HuGene_st:973004-HuGene_st:839631-HuGene_st:211964_at:316644- HuGene_st:1015712-HuGene_st COL4A1831741-HuGene_st:634068- COL4A1  1.243E−08 2.3004 3.03 87.5  77-94.2HuGene_st:816476-HuGene_st:1030276- HuGene_st:144637-HuGene_st:24196-HuGene_st:272762-HuGene_st:604042- HuGene_st:392785-HuGene_st:782962-HuGene_st:381555-HuGene_st:576333- HuGene_st:310901-HuGene_st:237606-HuGene_st:719873-HuGene_st:914012- HuGene_st:30564-HuGene_st:828024-HuGene_st:687375- HuGene_st:211981_at:211980_at:812556-HuGene_st:681655-HuGene_st:233652_at SPON2 173417-HuGene_st:845288-SPON2 1.9471E−08 2.3295 3.38 87.8 77.4-94.3HuGene_st:170898-HuGene_st:6411- HuGene_st:981126-HuGene_st:1098117-HuGene_st:1049111-HuGene_st:1018834- HuGene_st:300655-HuGene_st:45524-HuGene_st:256565-HuGene_st:533681- HuGene_st:346131-HuGene_st:251693-HuGene_st:937110-HuGene_st:347749- HuGene_st:645379-HuGene_st:107844-HuGene_st:396405- HuGene_st:218638_s_at:1569496_s_at COL5A2631247-HuGene_st:59739- COL5A2 5.7658E−08 2.2164 3.31 86.6  76-93.5HuGene_st:260654-HuGene_st:125943- HuGene_st:292068-HuGene_st:788391-HuGene_st:408375-HuGene_st:561511- HuGene_st:838505-HuGene_st:915389-HuGene_st:684636-HuGene_st:817279- HuGene_st:514415-HuGene_st:583557-HuGene_st:1009654-HuGene_st:416341- HuGene_st:260479-HuGene_st:292241-HuGene_st:1034540-HuGene_st:101178- HuGene_st:221730_at:221729_at FSTL11020674-HuGene_st:291086- FSTL1 7.8434E−08 2.2277 2.64 86.7 76.1-93.6HuGene_st:964097-HuGene_st:874354- HuGene_st:745908-HuGene_st:129330-HuGene_st:1039443-HuGene_st:855602- HuGene_st:494940-HuGene_st:666633-HuGene_st:10001-HuGene_st:654906- HuGene_st:322189-HuGene_st:891629-HuGene_st:225280-HuGene_st:67871- HuGene_st:965246-HuGene_st BGN722197-HuGene_st:1090822- BGN 9.6881E−08 2.2246 2.99 86.7 76.1-93.6HuGene_st:45294-HuGene_st:381650- HuGene_st:987820-HuGene_st:978124-HuGene_st:171694-HuGene_st:643594- HuGene_st:429977-HuGene_st:1096605-HuGene_st:861988-HuGene_st:164623- HuGene_st:201262_s_at:497499-HuGene_st:422042-HuGene_st:1051954- HuGene_st:262594-HuGene_st:279145-HuGene_st:838396-HuGene_st:298959- HuGene_st:11448-HuGene_st:111675-HuGene_st:213905_x_at:201261_x_at: 973749-HuGene_st FAP58645-HuGene_st:581008- IFIH1:FAP  1.358E−07 2.2253 4.88 86.7 76.1-93.6HuGene_st:284881-HuGene_st:1022038- HuGene_st:916010-HuGene_st:947725-HuGene_st:477772-HuGene_st:22772- HuGene_st:636840-HuGene_st:40379-HuGene_st:993707-HuGene_st:322964- HuGene_st:759386-HuGene_st:132558-HuGene_st:600137-HuGene_st:915847- HuGene_st:246189-HuGene_st:445095-HuGene_st:389696-HuGene_st:438119-HuGene_st:748913-HuGene_st:209955_s_at COL8A1333339-HuGene_st:214587_at:586420- COL8A1 3.6053E−07 2.1439 3.09 85.874.9-93  HuGene_st:103513-HuGene_st:651142-HuGene_st:617293-HuGene_st:107398- HuGene_st:79621-HuGene_st:806363-HuGene_st:327074-HuGene_st:41199- HuGene_st COL1A1767019-HuGene_st:654019- COL1A1 5.4426E−07 2.0142 3.29 84.3 73.1-92 HuGene_st:52480-HuGene_st:975188- HuGene_st:731985-HuGene_st:849620-HuGene_st:652845-HuGene_st:1077639- HuGene_st:149590-HuGene_st:788754-HuGene_st:1033327-HuGene_st:258815- HuGene_st:719132-HuGene_st:971026-HuGene_st:1061961-HuGene_st:435403- HuGene_st:498576-HuGene_st:1003153-HuGene_st:1029566-HuGene_st:487433- HuGene_st:165153-HuGene_st:125258-HuGene_st:217430_x_at:202310_s_at:1556 499_s_at:202311_s_at COL6A3312177-HuGene_st:24239- COL6A3 5.7026E−07 2.0313 2.73 84.5 73.5-92.1HuGene_st:337032-HuGene_st:31627- HuGene_st:72819-HuGene_st:85665-HuGene_st:51265-HuGene_st:315258- HuGene_st:423421-HuGene_st:976272-HuGene_st:627131-HuGene_st:547019- HuGene_st:482866-HuGene_st:871788-HuGene_st:273133-HuGene_st:945341- HuGene_st:223275-HuGene_st:768482-HuGene_st:618342-HuGene_st:993598- HuGene_st:716493-HuGene_st:153821-HuGene_st:201438_at COL1A2 918394-HuGene_st:75788- COL1A2:LOC7286288.8466E−07 2.0613 2.62 84.9 73.9-92.3HuGene_st:240155-HuGene_st:1079758- HuGene_st:174439-HuGene_st:133455-HuGene_st:720682-HuGene_st:723785- HuGene_st:1076123-HuGene_st:252002-HuGene_st:733200-HuGene_st:890123- HuGene_st:1070579-HuGene_st:52384-HuGene_st:928914-HuGene_st:257376- HuGene_st:355867-HuGene_st:472073-HuGene_st:349798-HuGene_st:153814- HuGene_st:825347-HuGene_st:202404_s_at:202403_s_at THY1 149448-HuGene_st:804495- THY11.0326E−06 1.9155 3.34 83.1 71.7-91.1 HuGene_st:287669-HuGene_st:329513-HuGene_st:432229-HuGene_st:834028- HuGene_st:462769-HuGene_st:408326-HuGene_st:603473-HuGene_st:497809- HuGene_st:301090-HuGene_st:606465-HuGene_st:208850_s_at:278686- HuGene_st:804789-HuGene_st:236645-HuGene_st:257047-HuGene_st:554409- HuGene_st:108391-HuGene_st:208851_s_at:213869_x_at:9087 85-HuGene_st:516398-HuGene_stCOL15A1 330621-HuGene_st:910395- COL15A1 1.0611E−06 2.0128 3.37 84.373.2-92  HuGene_st:811192-HuGene_st:294092-HuGene_st:958891-HuGene_st:407270- HuGene_st:423090-HuGene_st:1079597-HuGene_st:95084-HuGene_st:775288- HuGene_st:813875-HuGene_st:1001637-HuGene_st:49304-HuGene_st:970691- HuGene_st:346838-HuGene_st:91483-HuGene_st:528528-HuGene_st:453998- HuGene_st:254490-HuGene_st:203477_at:201064-HuGene_st CALD1 816439-HuGene_st:318906-CALD1 1.1059E−06 2.1159 1.7 85.5 74.6-92.8HuGene_st:558226-HuGene_st:755661- HuGene_st:519079-HuGene_st:1094139-HuGene_st:975649-HuGene_st:407536- HuGene_st:908350-HuGene_st:576686-HuGene_st:688034-HuGene_st:792918- HuGene_st:596642-HuGene_st:797317-HuGene_st:1023569-HuGene_st:450656- HuGene_st:231881_at:165931-HuGene_stIGFBP7 363517-HuGene_st:787689- IGFBP7 1.1574E−06 1.9989 1.91 84.172.9-91.8 HuGene_st:86333-HuGene_st:882867-HuGene_st:620969-HuGene_st:167271- HuGene_st:192752-HuGene_st:521467-HuGene_st:699448-HuGene_st:882712- HuGene_st:211325-HuGene_st:329940-HuGene_st:980809-HuGene_st:22805- HuGene_st:288233-HuGene_st:230028-HuGene_st:551901-HuGene_st:921418- HuGene_st:232544_at:969620-HuGene_st:985682-HuGene_st INHBA 1088123-HuGene_st:151327- INHBA1.1943E−06 2.0051 3.38 84.2  73-91.9 HuGene_st:363337-HuGene_st:874496-HuGene_st:402595-HuGene_st:289422- HuGene_st:838338-HuGene_st:746887-HuGene_st:623455-HuGene_st:395552- HuGene_st:865665-HuGene_st:328796-HuGene_st:1088331-HuGene_st:751719- HuGene_st:36929-HuGene_st:548889-HuGene_st:909672- HuGene_st:210511_s_at:344276-HuGene_st:204926_at:112496-HuGene_st COL12A1 905983-HuGene_st:794749-TMEM30A:COL12A1 1.2492E−06 2.03 4.16 84.5 73.4-92.1HuGene_st:1063560-HuGene_st:567963- HuGene_st:140178-HuGene_st:289954-HuGene_st:620694-HuGene_st:31736- HuGene_st:1009559-HuGene_st:435472-HuGene_st:415220-HuGene_st:447689- HuGene_st:405565-HuGene_st:180263-HuGene_st:595404-HuGene_st:759154- HuGene_st:419264-HuGene_st:319853-HuGene_st:225664_at:231879_at:874183- HuGene_st:913204-HuGene_st:231766_s_at:234951_s_at: 1057284-HuGene_st COL5A164984-HuGene_st:815841- COL5A1 1.6076E−06 1.9335 2.75 83.3  72-91.3HuGene_st:299983-HuGene_st:751853- HuGene_st:33784-HuGene_st:366345-HuGene_st:63200-HuGene_st:293998- HuGene_st:544275-HuGene_st:940629-HuGene_st:383962-HuGene_st:995286- HuGene_st:640471-HuGene_st:77586-HuGene_st:212489_at:633141- HuGene_st:203325_s_at:777727-HuGene_st:400357- HuGene_st:212488_at:291267-HuGene_st:285959-HuGene_st:886716- HuGene_st THBS2789762-HuGene_st:451028- THBS2 2.3382E−06 1.9035 6.5 82.9 71.6-91 HuGene_st:807449-HuGene_st:895973- HuGene_st:360384-HuGene_st:885374-HuGene_st:178235-HuGene_st:241784- HuGene_st:774957-HuGene_st:565405-HuGene_st:684979-HuGene_st:890746- HuGene_st:588267-HuGene_st:1033680-HuGene_st:387904-HuGene_st:1096131- HuGene_st:739113-HuGene_st:614690-HuGene_st:270369-HuGene_st:892858- HuGene_st TNC441837-HuGene_st:278723- TNC 3.7414E−06 1.9636 2.14 83.7 72.4-91.6HuGene_st:1030770-HuGene_st:767997- HuGene_st:514659-HuGene_st:873244-HuGene_st:837401-HuGene_st:621609- HuGene_st:888816-HuGene_st:660419-HuGene_st:889974-HuGene_st:780538- HuGene_st:157747-HuGene_st:908522-HuGene_st:263796-HuGene_st:280913- HuGene_st:201645_at:1016643-HuGene_st:243540_at:537682- HuGene_st:859608-HuGene_st:1079032-HuGene_st:458991-HuGene_st:241272_at MGP 148839-HuGene_st MGP:C12orf465.8225E−06 1.9994 2.62 84.1  73-91.9 COL3A1 410491-HuGene_st:718613-COL3A1 9.2906E−06 1.8484 2.32 82.2 70.8-90.5HuGene_st:1083201-HuGene_st:364429- HuGene_st:857967-HuGene_st:714343-HuGene_st:977793-HuGene_st:295757- HuGene_st:22453-HuGene_st:804687-HuGene_st:682411-HuGene_st:490951- HuGene_st:622631-HuGene_st:782663-HuGene_st:425013-HuGene_st:214723- HuGene_st:86407-HuGene_st:651938-HuGene_st:403765-HuGene_st:376736- HuGene_st:376290-HuGene_st:248520-HuGene_st SULF1 740854-HuGene_st:517026- SULF1 0.000014436 1.7533 2.8481 69.2-89.6 HuGene_st:933799-HuGene_st:72604-HuGene_st:1045684-HuGene_st:492122- HuGene_st:20084-HuGene_st:512275-HuGene_st:754502-HuGene_st:730003- HuGene_st:532406-HuGene_st:187508-HuGene_st:671986-HuGene_st:34752- HuGene_st:381424-HuGene_st:166879-HuGene_st:530745-HuGene_st:1018600-HuGene_st:212344_at:212354_at:482916- HuGene_st:212353_at HTRA1660603-HuGene_st:252436- HTRA1 0.000017178 1.7312 2.29 80.7 68.9-89.3HuGene_st:299850-HuGene_st:317595- HuGene_st:977390-HuGene_st:311841-HuGene_st:946172-HuGene_st:761215- 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HuGene_st:233555_s_at:430325-HuGene_st MMP2650123-HuGene_st:78720- MMP2 0.000025409 1.7328 3.02 80.7 68.8-89.3HuGene_st:168982-HuGene_st:598990- HuGene_st:346729-HuGene_st:356008-HuGene_st:821467-HuGene_st:905494- HuGene_st:568028-HuGene_st:711286-HuGene_st:666575-HuGene_st:208210- HuGene_st:20913-HuGene_st:382005-HuGene_st:186287-HuGene_st:355238- HuGene_st:60728-HuGene_st:1566677_at:1027926- HuGene_st:38019-HuGene_st:39088- HuGene_stTIMP3 686923-HuGene_st:767021- TIMP3 0.000026195 1.7785 2.56 81.369.6-89.8 HuGene_st:231888_at:201148_s_at:326731-HuGene_st:72249-HuGene_st:369765- HuGene_st:711121-HuGene_st:844721-HuGene_st:856619-HuGene_st:241221- HuGene_st:515184-HuGene_st:948668-HuGene_st:410881-HuGene_st COL6A2 404866-HuGene_st:420794- COL6A20.000029551 1.7418 1.67 80.8  69-89.4 HuGene_st:536399-HuGene_st:813295-HuGene_st:160736-HuGene_st:501950- HuGene_st:148827-HuGene_st:501480-HuGene_st:375216-HuGene_st:143566- HuGene_st:1086501-HuGene_st:475436-HuGene_st:794188-HuGene_st:704415- HuGene_st:213290_at LOC387763724781-HuGene_st:816467-HuGene_st LOC387763 0.00003052 1.8978 1.43 82.971.4-90.9 DKK3 573143-HuGene_st:509897- DKK3 0.000031838 1.7435 1.8680.8 69.1-89.5 HuGene_st:829432-HuGene_st:425906-HuGene_st:1076690-HuGene_st:480668- HuGene_st:302214-HuGene_st:673860-HuGene_st:584666-HuGene_st:966441- HuGene_st:138862-HuGene_st:19243-HuGene_st:600102-HuGene_st:778172- HuGene_st:387542-HuGene_st:202196_s_at:230508_at:86457- HuGene_st CTSK592586-HuGene_st:682010- CTSK 0.000039778 1.7156 2.16 80.4 68.8-89.1HuGene_st:30909-HuGene_st:235976- HuGene_st:913861-HuGene_st:25198-HuGene_st:96515-HuGene_st:221416- HuGene_st:341005-HuGene_st:371949-HuGene_st:796154-HuGene_st:555578- HuGene_st:416489-HuGene_st:123013-HuGene_st:50644-HuGene_st:636682- HuGene_st:63600-HuGene_st:356075-HuGene_st:321593-HuGene_st LOC541471 19600-HuGene_st:149287- MGC4677,0.000041139 1.804 1.45 81.6 69.9-90  HuGene_st:916693-HuGene_st:569637-MGC4677:LOC541471 HuGene_st:868769-HuGene_st:469295-HuGene_st:277416-HuGene_st:71551- HuGene_st:1558836_at:129947-HuGene_st:644672-HuGene_st:276744- HuGene_st:873188-HuGene_st:830227-HuGene_st:101170-HuGene_st:624891- HuGene_st:85671-HuGene_st:236489-HuGene_st:709116-HuGene_st:279980- HuGene_st:812194-HuGene_st CHI3L1561691-HuGene_st:116044- CHI3L1:MYBPH 0.000051515 1.6351 3.06 79.367.4-88.3 HuGene_st:261087-HuGene_st:57128-HuGene_st:970931-HuGene_st:518568- HuGene_st:362438-HuGene_st:388847-HuGene_st:738096- HuGene_st:209396_s_at:171378-HuGene_st:968794-HuGene_st:477315- HuGene_st:852388-HuGene_st:90371-HuGene_st:209395_at:657732- HuGene_st:1050574-HuGene_st:1074100-HuGene_st:219902-HuGene_st:744799- HuGene_st CD93392816-HuGene_st:131787- CD93 0.000051891 1.6662 2.36 79.8 67.8-88.6HuGene_st:900048-HuGene_st:1024597- HuGene_st:449159-HuGene_st:937408-HuGene_st:835153-HuGene_st:231835- HuGene_st:1084191-HuGene_st:970338-HuGene_st:835439-HuGene_st:345929- 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HuGene_st:316216-HuGene_st:971683-HuGene_st:394963-HuGene_st:600623- HuGene_st:169932-HuGene_st:941525-HuGene_st:202765_s_at:1094040- HuGene_st:192231-HuGene_st:235318_at MMP37912-HuGene_st:438906- MMP3 0.0001 1.6224 6.68 79.1 67.2-88.1HuGene_st:483424-HuGene_st:634624- HuGene_st:191436-HuGene_st:542596-HuGene_st:664043-HuGene_st:766524- HuGene_st:134417-HuGene_st:945713-HuGene_st:149350-HuGene_st:357556- HuGene_st:206224-HuGene_st:560206-HuGene_st:822598-HuGene_st:200029- HuGene_st:701539-HuGene_st:526573-HuGene_st:35444-HuGene_st ISLR 1034362-HuGene_st:755902- ISLR 0.00011.6424 1.87 79.4 67.4-88.4 HuGene_st:864958-HuGene_st:599962-HuGene_st:207191_s_at:256349- HuGene_st:223953-HuGene_st:172743-HuGene_st:46312-HuGene_st:11475- HuGene_st:500169-HuGene_st COL6A1138884-HuGene_st:100156- COL6A1 0.0001 1.7314 1.58 80.7 68.9-89.3HuGene_st:694215-HuGene_st:133534- HuGene_st:354247-HuGene_st:737256-HuGene_st:214200_s_at:212939_at: 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HuGene_st:412306-HuGene_st:922332-HuGene_st:491408-HuGene_st:929740- HuGene_st:276131-HuGene_st:201952-HuGene_st VIM 1093618-HuGene_st:398387- VIM 0.0008 1.4804 1.48 7764.9-86.5 HuGene_st:837477-HuGene_st:1079757-HuGene_st:339807-HuGene_st:302722- HuGene_st:139661-HuGene_st:436158-HuGene_st:564251-HuGene_st:234475- HuGene_st:770617-HuGene_st:155888-HuGene_st:319318-HuGene_st:527110- HuGene_st:994975-HuGene_st:192324-HuGene_st ASPN 720939-HuGene_st:96944- ASPN 0.0009 1.4011 2.75 75.863.5-85.6 HuGene_st:224396_s_at:640448-HuGene_st:1055545-HuGene_st:447994- HuGene_st:835521-HuGene_st:567513-HuGene_st:546047- HuGene_st:219087_at:673 620-HuGene_st HNT291569-HuGene_st:1099035- HNT 0.001 1.425 2.26 76.2 63.8-85.8HuGene_st:237480- HuGene_st:222020_s_at:959054-HuGene_st:941200-HuGene_st:715332- HuGene_st:761810-HuGene_st:673027-HuGene_st:653559- HuGene_st:241934_at:403764-HuGene_st:719722-HuGene_st:227566_at GJA1 210697-HuGene_st:348617- GJA10.0013 1.4083 1.63 75.9 63.7-85.6 HuGene_st:100706-HuGene_st:202715-HuGene_st:817684-HuGene_st:851453- HuGene_st:317083-HuGene_st:852817-HuGene_st:150947-HuGene_st:491742- HuGene_st:612542-HuGene_st:352375-HuGene_st:684816-HuGene_st MSN 77554-HuGene_st:103225- MSN  1.40E−031.4927 1.36 77.2 65.1-86.7 HuGene_st:1038630-HuGene_st:555838-HuGene_st:250445-HuGene_st:770842- HuGene_st:240960_at:905037-HuGene_st:693942-HuGene_st:788076- HuGene_st:102934-HuGene_st:686613-HuGene_st SFRP4 965138-HuGene_st:512201- SFRP4 0.0015 1.407 2.2 75.963.5-85.5 HuGene_st:321583-HuGene_st:784119-HuGene_st:4568-HuGene_st:1073348- HuGene_st:606783-HuGene_st:203475-HuGene_st:779727-HuGene_st:236875- HuGene_st:674172-HuGene_st:204051_s_at:1084814- HuGene_st CTGF 418229-HuGene_st:547481-CTGF 0.0015 1.334 1.78 74.8 62.4-84.6 HuGene_st:661089-HuGene_st:338622-HuGene_st:353624-HuGene_st:466254- HuGene_st:691815-HuGene_st:156933-HuGene_st:1031177-HuGene_st:265466- HuGene_st:1079612-HuGene_st:1073900-HuGene_st:1080114-HuGene_st FCGR3B p75320-HuGene_st:483078- FCGR3B0.0026 1.232 2.14 73.1 60.5-83.3 HuGene_st:897088-HuGene_st:891504-HuGene_st:288407-HuGene_st:367930- HuGene_st:512343-HuGene_st:524627-HuGene_st:290249- HuGene_st:204007_at:993144-HuGene_st:1084295-HuGene_st:606544- HuGene_st:160442-HuGene_st:974942-HuGene_st:582410-HuGene_st:117174- HuGene_st LOXL1244262-HuGene_st:240421- LOXL1 0.0027 1.4045 1.33 75.9 63.7-85.5HuGene_st:999775-HuGene_st LUM 253522-HuGene_st:646969- LUM 0.00291.3426 2.18 74.9 62.5-84.7 HuGene_st:566007-HuGene_st:629878-HuGene_st:346266-HuGene_st:749731- HuGene_st:848594-HuGene_st:781980-HuGene_st:838285-HuGene_st:594339- HuGene_st:1095278-HuGene_st:450762-HuGene_st:205322-HuGene_st:130751- HuGene_st:183047-HuGene_st:15672-HuGene_st SERPINF1 837342-HuGene_st SERPINF1 0.0031 1.2108 1.76 72.860.2-83  MXRA5 319799-HuGene_st:432137- MXRA5 0.0034 1.2959 1.62 74.161.6-84.1 HuGene_st:408065-HuGene_st:291182-HuGene_st:549236-HuGene_st:217706- HuGene_st:260019-HuGene_st:1079370-HuGene_st:216837-HuGene_st:607674- HuGene_st:829671-HuGene_st:348569-HuGene_st:357055-HuGene_st:394366- HuGene_st:192313-HuGene_st:124763-HuGene_st POSTN 954838-HuGene_st:153510- POSTN 0.005 1.301 2.58 74.261.7-84.3 HuGene_st:538299-HuGene_st:649547-HuGene_st:779754-HuGene_st:106590- HuGene_st:636479-HuGene_st:874100-HuGene_st:13993-HuGene_st:417058- HuGene_st:724846-HuGene_st:588010-HuGene_st:608772- HuGene_st:210809_s_at:743877-HuGene_st:713459-HuGene_st:713707- HuGene_st:753556-HuGene_st:776445-HuGene_st:388659-HuGene_st TAGLN 613243-HuGene_st:823959- TAGLN 0.00511.1811 2.19 72.3 59.6-82.6 HuGene_st:898711-HuGene_st:505391-HuGene_st:26929-HuGene_st:458482- HuGene_st:66114-HuGene_st:304704-HuGene_st:543865- HuGene_st:226523_at:270642-HuGene_st:179049-HuGene_st:279405- HuGene_st:902958-HuGene_st:931316-HuGene_st NNMT 231559_at:588888-HuGene_st:160284- NNMT 0.0054 1.22251.44 72.9 60.5-83.2 HuGene_st:591616-HuGene_st:968910-HuGene_st:789017-HuGene_st:218836- HuGene_st:775762-HuGene_st:202238_s_at:95357- HuGene_st:1098599-HuGene_st:793701-HuGene_st IL8 471213-HuGene_st:373132-HuGene_st LOC731467:C6orf142:0.0062 1.6808 1.33 80 68.1-88.7 CCDC42:IFI6:TRBV21-1:H2AFZ:RNF20:TRBV5-4: TRBC1:TRBV3-1:TRBV19: TRBV7-2:IL23A GREM1651822-HuGene_st:546941- GREM1 0.007 1.3044 1.31 74.3 61.8-84.2HuGene_st:639839-HuGene_st:326978- HuGene_st:593695-HuGene_st:127360-HuGene_st:407017-HuGene_st:1081939- HuGene_st:345681-HuGene_st:292333-HuGene_st:864620-HuGene_st:2445- HuGene_st:556201-HuGene_st:569365-HuGene_st:411208-HuGene_st:330742- HuGene_st CIS947234-HuGene_st:962144- C1S 0.0088 1.3551 1.77 75.1 62.8-84.9HuGene_st:567397-HuGene_st:490300- HuGene_st:459367-HuGene_st:1059233-HuGene_st:915378-HuGene_st:682561- HuGene_st:881984-HuGene_st:332123-HuGene_st:37033-HuGene_st:433793- HuGene_st:564959-HuGene_st:240802-HuGene_st:245571-HuGene_st:156493- HuGene_st:186313-HuGene_st:866948-HuGene_st:661278-HuGene_st:665064- HuGene_st:615340-HuGene_st:981405-HuGene_st:127169-HuGene_st:224321- HuGene_st:426716-HuGene_st:905688-HuGene_st:1009344-HuGene_st:184395- HuGene_st TIMP2310783-HuGene_st:526357- TIMP2 0.0097 1.1623 1.72 71.9 59.4-82.3HuGene_st:965142-HuGene_st:463158- HuGene_st:563754-HuGene_st:914626-HuGene_st:106688-HuGene_st:1087828- HuGene_st:740790-HuGene_st:799495-HuGene_st SPP1 87046-HuGene_st:904296- SPP1 0.0109 1.0677 3.91 70.357.6-80.9 HuGene_st:809583-HuGene_st:44881-HuGene_st:1568574_x_at:459132- HuGene_st:963342-HuGene_st:909306-HuGene_st:1070547-HuGene_st:31302- HuGene_st:975259-HuGene_st:743585-HuGene_st:530424-HuGene_st:709614- HuGene_st:1022539-HuGene_st:575437-HuGene_st:809262-HuGene_st:259921- HuGene_st SCD214388-HuGene_st:1054693- SCD:LOC651109:  1.27E−02 1.073 2.33 70.457.7-81  HuGene_st:433956-HuGene_st:1088784- LOC645313HuGene_st:1019041-HuGene_st:698268- HuGene_st:64902-HuGene_st:749928-HuGene_st:713000-HuGene_st:562893- HuGene_st MYL9206106-HuGene_st:608837- MYL9 0.0131 1.1754 1.37 72.2 59.6-82.4HuGene_st:706186-HuGene_st:874422- HuGene_st:543240-HuGene_st:676360-HuGene_st:117460-HuGene_st:404703- HuGene_st:979054-HuGene_st:244149_at:467647- HuGene_st:925187-HuGene_st:173220-HuGene_st:923797-HuGene_st CD163 967100-HuGene_st:180883- CD163 0.01461.1667 2.19 72 59.4-82.3 HuGene_st:900552-HuGene_st:662901-HuGene_st:217692-HuGene_st:74082- HuGene_st:620892-HuGene_st:899841-HuGene_st:97726-HuGene_st S100A8 508168-HuGene_st:306748- S100A8 0.01481.1001 3.17 70.9 58.3-81.3 HuGene_st:473960-HuGene_st:98947-HuGene_st:777038-HuGene_st:233365- HuGene_st:671798-HuGene_st:214328-HuGene_st:214370_at:368299- HuGene_st:16960-HuGene_st:627642-HuGene_st:669207-HuGene_st:75346- HuGene_st:521635-HuGene_st:215650-HuGene_st:618819-HuGene_st CYR61 709380-HuGene_st:788428- CYR61 0.0151.093 1.69 70.8 58.2-81.3 HuGene_st:385534-HuGene_st:924057-HuGene_st:951763-HuGene_st:48239- HuGene_st:462225-HuGene_st:789527-HuGene_st:673588-HuGene_st:306375- HuGene_st MAFB 883249-HuGene_st MAFB0.0182 1.1589 1.48 71.9 59.3-82.3 APOE 555956-HuGene_st:99757-HuGene_stAPOE 0.0285 1.1117 1.43 71.1 58.6-81.5 DCN570449-HuGene_st:1067446-HuGene_st DCN 0.0364 1.0819 1.29 70.6  58-81.1G0S2 888942-HuGene_st:346957- G0S2 0.0383 0.9923 1.53 69 56.3-79.9HuGene_st:62728-HuGene_st:334340- HuGene_st:897401-HuGene_st CDH1160296-HuGene_st:609892- CDH11 0.0384 1.01 1.98 69.3 56.7-80 HuGene_st:167614-HuGene_st:184349- HuGene_st:546348-HuGene_st:960949-HuGene_st:583244-HuGene_st:599824- HuGene_st:626011-HuGene_st:96018-HuGene_st:217538-HuGene_st:180379- HuGene_st SQLE861626-HuGene_st:198540- SQLE 0.041 1.0133 2.15 69.4 56.7-80.1HuGene_st:1010566-HuGene_st:895693- HuGene_st:967759-HuGene_st:894379-HuGene_st:827097-HuGene_st GPNMB NA GPNMB 0.0623 1.0155 1.52 69.456.8-80.1 KIAA1913 NA KIAA1913 0.1061 0.9593 1.2 68.4 55.7-79.3 SFRP2 NASFRP2 0.1336 0.9696 1.24 68.6  56-79.4 SMOC2 NA SMOC2 0.2175 0.6581 2.0662.9  50-74.4 SERPING1 NA SERPING1  2.64E−01 0.7805 1.26 65.2 52.5-76.5EFEMP1 NA EFEMP1 0.4911 0.6831 1.27 63.4 50.5-74.9 TYROBP NA TYROBP0.4923 0.7065 1.23 63.8 51.1-75.2 PLOD2 NA PLOD2 0.5151 0.7775 1.51 65.152.3-76.3

TABLE 9 SEQ ID Probe NO: Set ID Target Sequence   1 200660caaggctgggccgggaagggcgtgggttgaggagaggctccagacccgcacgccgcgcgcacagagctctcagc_atgccgctcccagccacagcctcccgcgcctcgctcagctccaacatggcaaaaatctccagccctacagagactgagcggtgcatcgagtccctgattgctgtcttccagaagtatgctggaaaggatggttataactacactctctccaagacagagttcctaagcttcatgaatacagaactagctgccttcacaaagaaccagaaggaccctggtgtccttgaccgcatgatgaagaaactggacaccaacagtgatggtcagctagatttctcagaatttcttaatctgattggtggcctagctatggcttgccatgactccttcctcaaggctgtcccttcccagaagcggacctgaggaccc   2 200665gttggttcaaacttttgggagcacggactgtcagttctctgggaagtggtcagcgcatcctgcagggcttctcctcctctgt_s_atcttttggagaaccagggctcttctcaggggctctagggactgccaggctgtttcagccaggaaggccaaaatcaagagtgagatgtagaaagttgtaaaatagaaaaagtggagttggtgaatcggttgttctttcctcacatttggatgattgtcataaggtttttagcatgttcctccttttcttcaccctcccctttgttcttctattaatcaagagaaacttcaaagttaatgggatggtcggatctcacaggctgagaactcgttcacctccaagcatttcatgaaaaagctgcttcttattaatcatacaaactctcaccatgatgtg   3 200832aaaagcgaggtggccatgttatgctggtggttgccagggcctccaaccactgtgccactgacttgctgtgtgaccctggg_s_atcaagtcacttaactataaggtgcctcagttttccttctgttaaaatggggataataatactgacctacctcaaagggcagttttgaggcatgactaatgctttttagaaagcattttgggatccttcagcacaggaattctcaagacctgagtattttttataataggaatgtccaccatgaacttgatacgtccgtgtgtcccagatgctgtcattagtctatatggttctccaagaaactgaatgaatccattggagaagcggtggataactagccagacaaaatttgagaatacataaacaacgcattgccacggaaacatacagaggatgccttttctgtgattgggtgggattttttccctttttatgtgggatatagtagttacttgtgacaagaataattttggaataatttctattaatatcaactctgaagctaattgtactaatctgagat   4 200903gcagcgggaacagagtaccctcttcaagccccggtcatgatggaggtcccagccacagggaaccatgagctcagtgg_s_attcttggaacagctcactaagtcagtccttccttagcctggaagccagtagtggagtcacaaagcccatgtgttttgccatctaggccttcacctggtctgtggacttatacctgtgtgcttggtttacaggtccagtggttcttcagcccatgacagatgagaaggggctatattgaagggcaaagaggaactgttgtttgaattttcctgagagcctggcttagtgctgggccttctcttaaacctcattacaatgaggttagtacttttagtccctgt   5 201014agtgttgatgggctctacttctgatcttggtcactgtgaaaaaatcaagaaggcctgtggaaattttggcattccatgtgaac_s_atttcgagtaacatctgcgcataaaggaccagatgaaactctgaggattaaagctgagtatgaaggggatggcattcctactgtatttgtggcagtggcaggcagaagtaatggtttgggaccagtgatgtctgggaacactgcatatccagttatcagc  6 201112agatctgtgcggttggcataaccaacttactaacagaatgtcccccaatgatggacactgagtataccaaactgtggactc_s_atcattattacagtctttgattggtctttttgagttacccgaagatgataccattcctgatgaggaacattttattgacatagaagatacaccaggatatcagactgccttctcacagttggcatttgctgggaaaaaagagcatgatcctgtaggtcaaatggtgaataaccccaaaattcacctggcacagtcacttcacatgttgtctaccgcctgtccaggaagggttc   7201195tcagaaggtaggggccgtgtcccgcggtgctgactgaggcctgcttccccctccccctcctgctgtgctggaattccaca_s_atgggaccagggccaccgcaggggactgtctcagaagacttgatttttccgtccctttttctccacactccactgacaaacgtccccagcggtttccacttgtgggcttcaggtgttttcaagcacaacccaccacaacaagcaagtgcattttcagtcgttgtgcttttttgttttgtgctaacgtcttactaatttaaagatgctgtcggcaccatgtttatttatttccagtggtcatgctcagccttgctgctctgcgtggcgcaggtgccatgcctgctccctgtctgtgtcccagccacgcagggccatccactgtgacgtcggccgaccaggctggacaccctctgccgagtaatgacgtgtgtggctgggaccttctttattctgtgttaatggctaacctgttacactgggctgggttgggtagggtgttctggc   8 201261tctctctttctgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtcttgtgcttcctcagacctttctcgcttctgagcttggt_x_atggcctgttccctccatctctccgaacctggcttcgcctgtccctttcactccacaccctctggccttctgccttgagctgggactgctttctgtctgtccggcctgcacccagcccctgcccacaaaaccccagggacagcggtctccccagcctgccctgctcaggccttgcccccaaacctgtactgtcccggaggaggttgggaggtggaggcccagcatcccgcgcagatgacaccatcaaccgccagagtcccagacaccggttttcctagaagcccctcacccccactggcccactggtggctaggtctccccttatccttctggtccagcgcaaggaggggctgcttctgaggtcggtggctgtctttccattaaagaaacacc  9 201292tacagatactctactacactcagcctcttatgtgccaagtttttctttaagcaatgagaaattgctcatgttcttcatcttctcaa_atatcatcagaggccgaagaaaaacactttggctgtgtctataacttgacacagtcaatagaatgaagaaaattagagtagttatgtgattatttcagctcttgacctgtcccctctggctgcctctgagtctgaatctcccaaagagagaaaccaatttctaagaggactggattgcagaagactcggggacaacatttgatccaagatcttaaatgttatattgataaccatgctcagcaatgagctattagattcattttgggaaatctccataatttcaatttgtaaactttgttaagacctgtctacattgttatatg 10 201328agcatcggagccattcattcggagaaaacgttttgatcaaaatggagacttttgtagtcgtttcaaaagagcacctgagtca_attgtgtattcccggcnnnctttataaatgacccggtcaagttggtttcaaagtncgacaggcttgtctgtttactagctgcgtggccttggacgggtggctgacatctgtaaagaatcctcctgtgatgaaactgaggaatcgggtggccgggcaagctgggaagagcaaagccagnagctgcgctgcctcaatacccacaaaagaccattcccagtatacataagcacaggatgtttttctcaagagggatgtatttatcacttggacatctgtttataatataaacagacatgtgactgggaacatcttgctgccaaaagaatcctaggcagtggctcattgtatgtgaggttgaaccacgtgaaattgccaatattaggctggcttttatctacaaagaaggagtttcatggggttcagcctaacagttatggaaactacagtccttataaaccattggcatg  11 201338gatgtatgtcgctgtccaagagaaggctgtggaagaacctatacaactgtgtttaatctccaaagccatatcctctccttcc_x_atatgaggaaagccgcccttttgtgtgtgaacatgctggctgtggcaaaacatttgcaatgaaacaaagtctcactaggcatgctgttgtacatgatcctgacaagaagaaaatgaagctcaaagtcaaaaaatctcgtgaaaaacgggagtttggcctctcatctcagtggatatatcctcccaaaaggaaacaagggcaaggcttatctttgtgtcaaaacggagagtcacccaactgtgtggaagacaagatgctctcgacagttgcagtacttacccttggctaagaactgcactgctttgtttaaaggactgcagaccaaggagtcgagctttctctca  12 201341ggtctgttcttgaatcctctattaattactgtgtgtgagccagagggagctgtggtaagggttgggcccccagcctgtagg_atgaactttctggactcccactctttgaatcgatataggcatttggtctcactacttgaccattctcaccctgtgaaacgtcccacactttgaagcaaatacaattcacagcacagtacacacaaaaaccaggccttaagacagagaaggttcttcttattttgtgggctggttgctgtagaaacatataacaaagggcagccctccacttctggtataattgtgtagccccttttctttgggcttgacacctgtcttgaataagagtgattagagctgcataatgtccctctctt  13 201416gaggtcagatttggagcttctcattgcacgcggagattattattgcatcgggttccaagccaatgggaagcccggggga_atggggtttggcatgaggaagcgttggttacagcagctgattggctgcagccaagactgtgaaaggataaagaggcgcgaggcggaattggggtctgctctaagctgcagcaagagaaactgtgtgtgaggggaagaggcctgtttcgctgtcgggtctctagttcttgcacgctctttaagagtctgcactggaggaactcctgccattaccagctcccttcttgcagaagggagggggaaacatacatttattcatgccagtctgttgcatgcaggctttnnggcttcctaccttgcaacaaaataattgcaccaactccttagtgccgattccgcccacagagagtcctggagccacagtcttttttgctttgcattgtaggagagggactaagtgctagagactatgtcgctttcctgagctaccgagagcgctcgtgaactggaatcaact  14 201417gtaaaccacatcttttttgcactttttttataagcaaaaacgtgccgtttaaaccactggatctatctaaatgccgatttgagttc_atgcgacactatgtactgcgtttttcattcttgtatttgactatttaatcctttctacttgtcgctaaatataattgttttagtcttatggcatgatgatagcatatgtgttcaggtttatagctgttgtgtttaaaaattgaaaaaagtggaaaacatctttgtacatttaagtctgtattataataagcaaaaagattgtgtgtatgtatgtttaatataacatgacaggcactaggacgtctgcctttttaaggcagttccgttaagggtttttgtttttaaacttttttttgccatccatcctgtgcaatatgccgtgta  15201468gatgacttaccatgggatggggtccagtcccatgaccttggggtacaattgtaaacctagagttttatcaactttggtgaac_s_atagttttggcataatagtcaatttctacactggaagtcatctcattccactgttggtattatataattcaaggagaatatgataaaacactgccctcttgtggtgcattgaaagaagagatgagaaatgatgaaaaggttgcctgaaaaatgggagacagcctcttacttgccaagaaaatgaagggattggaccgagctggaaaacctcctttaccagatgctgactggcactggtggtttttgctctcgacatatccacaatagctgacggctgggtgtttcagtttgcaaaatattttgttgccttcatcttcactgcaattttgtgta 16 201479ttcagacccagtaactgtccgcagctgtctgctagtggttgtcttaacatcgtagtcctagtttgcattttttaaatcccctctgt_atttaaaaggtttgtaaaacaaaaacaaaaaactaagtctgctcagtgaaatgctgtagaaccctaaataagtggtagaagagtgtcactgaattttgtctctgaattcagtataactgagttttgtccatgctggtgtctgggttataggcctgatgggcctggtagttttccatcttgttctggcctagaggtcagtcctttgcacttcctcaaagcttgtgtacagtgctcacctaaatccatctgactacttgttcctgtgccctcttgttttaggcctcgtttacttttaaaaaatgaaattgttcattgctgggagaagaatgttgtaatttttacttattaaagtcaacttgttaagttttttatgtattcctgttgggttttcttgttg  17 201506acaggaggaatgcaccacggcagctctccgccaatttctctcagatttccacagagactgtttgaatgttttcaaaaccaa_atgtatcacactttaatgtacatgggccgcaccataatgagatgtgagccttgtgcatgtgggggaggagggagagagatgtactttttaaatcatgaccccctaaacatggctgttaacccactgcatgcagaaacttggatgtcactgcctgacattcacttccagagaggacctatcccaaatgtggaattgactgcctatgccaagtccctggaaaaggagcttcagtattgtggggctcataaaacatgaatcaagcaatccagcctcatgggaagtcctggcacagtttttgtaaagcccttgcacagctggagaaatggcatcattataagctatgagttgaaatgttctgtcaaatgtgtctcacatctacacgtggcttggaggcttttatggggccctgtccaggtagaaaagaaatggtatgtagagcttagatttccctattgtgacagagcc  18 201563aggaaactgctacttgtggacctcaccagagaccaggagggtttggttagctcacaggacttcccccaccccagaagat_attagcatcccatactagactcatactcaactcaactaggctcatactcaattgatggttattagacaattccatttctttctggttattataaacagaaaatctttcctcttctcattaccagtaaaggctcttggtatctttctgttggaatgatttctatgaacttgtcttattttaatggtgggttttttttctggtaagatttagacctaaatcgcatcatgccaacttgtgactttgagactattcatcaagaatgaggatatagtagccatgacatagcttgagctatagcctttaattccttactttggctatgggtggagggtgagtttgaagaggttctgattttcttgtaacctggga  19 201577gattccgccttgttggtctgaaattcatgcaagcttccgaagatcttctcaaggaacactacgttgacctgaaggaccgtcc_atattctttgccggcctggtgaaatacatgcactcagggccggtagttgccatggtctgggaggggctgaatgtggtgaagacgggccgagtcatgctcggggagaccaaccctgcagactccaagcctgggaccatccgtggagacttctgcatacaagttggcaggaacattatacatggcagtgattctgtggagagtgcagagaaggagatcggcttgtggtttcaccctgaggaactggtagattacacgagctgtgctcagaactggatctatgaatgacaggagggcagaccacattgcttttcacatccatttcccctccttcccatgggcagaggaccaggctgtaggaaatctagttatttacaggaacttcatcataatttggagggaagctcttggagctgtgagttctccctgtacagtgttaccatc  20 201601agaaaaccacacttctcataccttcactcaacacttccttccccaaagccagaagatgcacaaggaggaacatgaggtg_x_atgctgtgctgggggcaccccccagcaccatccttccaaggtccaccgtgattaacatccacagcgagacctccgtgcccgaccatgtcgtctggtccctgttcaacaccctcttcttgaactggtgctgtctgggcttcatagcattcgcctactccgtaaagtctagggacaggaagatggttggcgacgtgaccggggcccaggcctatgcctccaccgccaagtgcctgaacatctgggccctgattctgggcatcctcatgaccattggattcatcctgttactggtattcggctctgtaacagtctaccatattatgttacagataatacaggaaaaacggggttactagtagccgcccatagcctgcaacctttgcactccactgtgcaatgctggcc  21 201656gtagtgccactgttgttttggggggggctttttttctttttccggaaaatccttaaaccttaagatactaaggacgttgttttggt_attgtacttggaattcttagtcacaaaatatattttgtttacaaaaatttctgtaaaacaggttataacagtgtttaaagtctcagtttcttgcttggggaacttgtgtccctaatgtgttagattgctagattgctaaggagctgatacttgacagttttttagacctgtgttactaaaaaaaagatgaatgtcggaaaagggtgttgggagggtggtcaacaaagaaacaaagatgttatggtgtttagacttatggttgttaaaaatgtcatctcaagtcaagtcactggtctgtttgcatttgatacatttttgtactaactagcattgtaaaattatttcatgattagaaattacctgtggatatttgtataaaagtgtgaaataaattttttataaaagtgttcattgtttcgtaacacagcatt  22 201666tcagggccaagttcgtggggacaccagaagtcaaccagaccaccttataccagcgttatgagatcaagatgaccaagat_atgtataaagggttccaagccttaggggatgccgctgacatccggttcgtctacacccccgccatggagagtgtctgcggatacttccacaggtcccacaaccgcagcgaggagtttctcattgctggaaaactgcaggatggactcttgcacatcactacctgcagtttcgtggctccctggaacagcctgagcttagctcagcgccggggcttcaccaagacctacactgttggctgtgaggaatgcacagtgtttccctgtttatccatcccctgcaaactgcagagtggcactcattgcttgtggacggacc 23 201925gtgatttttttccacaagtttctgtaatgttatttccacttataaaggaaataaaaaatgaaaaacattatttggatatcaaaagc_s_ataaataaaaacccaattcagtctcttctaagcaaaattgctaaagagagatgaaccacattataaagtaatctttggctgtaaggcattttcatctttccttcgggaggcaaaatattttaaaggtaaaacatgctggtgaaccaggggtgttgatggtgataagggaggaatatagaatgaaagactgaatcttcctttgttgcacaaatagagtttggaaaaagcctgtgaaaggtgtcttctttgacttaatgtctttaaaagtatccagagatactacaatattaacataagaaaagattatatattatttctgaatcgagatgtccatagtcaaatttgtaa  24 201926gagagcactctatttattgtactgtgaataatgatgaaggagagtggagtggcccaccacctgaatgcagaggaaaatct_s_atctaacttccaaggtcccaccaacagttcagaaacctaccacagtaaatgttccaactacagaagtctcaccaacttctcagaaaaccaccacaaaaaccaccacaccaaatgctcaagcaacacggagtacacctgtttccaggacaaccaagcattttcatgaaacaaccccaaataaaggaagtggaaccacttcaggtactacccgtcttctatctgggcacacgtgtttcacgttgacaggtttgcttgggacgctagtaaccatgggcttgctgacttagccaaagaagagttaagaagaaaatacacacaagtatacagactgttcctagtttcttagactta  25 202286gtatgacaacccgggatcgtttgcaagtaactgaatccattgcgacattgtgaaggcttaaatgagtttagatgggaaata_s_atgcgttgttatcgccttgggtttaaattatttgatgagttccacttgtatcatggcctacccgaggagaagaggagtttgttaactgggcctatgtagtagcctcatttaccatcgtttgtattactgaccacatatgcttgtcactgggaaagaagcctgtttcagctgcctgaacgcagtttggatgtctttgaggacagacattgcccggaaactcagtctatttattcttcagcttgccc 26 202310tggcctacatggaccagcagactggcaacctcaagaaggccctgctcctccagggctccaacgagatcgagatccgc_s_atgccgagggcaacagccgcttcacctacagcgtcactgtcgatggctgcacgagtcacaccggagcctggggcaagacagtgattgaatacaaaaccaccaagacctcccgcctgcccatcatcgatgtggcccccttggacgttggtgccccagaccaggaattcggcttcgacgttggccctgtctgcttcctgtaaactccctccatcccaacctggctccctcccacccaaccaactttccccccaacccggaaacagacaagcaacccaaactgaaccccctcaaaagccaaaaaatgggagacaatttcacatggactttggaaaatatttttttcctttgcattcatctctcaaacttagtttttatctttgaccaaccgaacatgacca 27 202311gctccccatttttataccaaaggtgctacatctatgtgatgggtggggtggggagggaatcactggtgctatagaaattga_s_atgatgcccccccaggccagcaaatgttcctttttgttcaaagtctatttttattccttgatattttttntttntttttttttttttttgtggatggggacttgtgaatttttctaaaggtgctatttaacatgggaggagagcgtgtgcggctccagcccagcccgctgctcactttccaccctctctccacctgcctctggcttctcaggcctctgctctccgacctctctcctctgaaaccctcctccacagctgcagcccatcctcccggctccctcctagtctgtcctgcgtcctctgtccccgggtttcagagacaacttcccaaagcacaaagcagtttttncccctaggggtgggaggaagcaaaagactctgtacctattttgt  28 202403aacctgaaaacatcccagccaagaactggtataggagctccaaggacaagaaacacgtctggctaggagaaactatca_s_atatgctggcagccagtttgaatataatgtagaaggagtgacttccaaggaaatggctacccaacttgccttcatgcgcctgctggccaactatgcctctcagaacatcacctaccactgcaagaacagcattgcatacatggatgaggagactggcaacctgaaaaaggctgtcattctacagggctctaatgatgttgaacttgttgctgagggcaacagcaggttcacttacactgttcttgtagatggctgctctaaaaagacaaatgaatggggaaagacaatcattgaatacaaaacaaataagccatcacgcctgcccttccttgatattgcacctttggacatcggtggtgctgaccaggaattctttgtggacattggcccagtctgtt 29 202404actttcccatgagtgtgatccacattgttaggtgctgacctagacagagatgaactgaggtccttgttttgttttgttcataata_s_atcaaaggtgctaattaatagtatttcagatacttgaagaatgttgatggtgctagaagaatttgagaagaaatactcctgtattgagttgtatcgtgtggtgtattttttaaaaaatttgatttagcattcatattttccatcttattcccaattaaaagtatgcagattatttgcccaaagttgtcctcttcttcagattcagcatttgttctttgccagtctcattttcatcttcttccatggttccacagaagctttgtttcttgggca  30 202431gcaacaaccgaaaatgcaccagccccaggtcctcggacaccgaggagaatgtcaagaggcgaacacacaacgtctt_s_atggagcgccagaggaggaacgagctaaaacggagcttttttgccctgcgtgaccagatcccggagttggaaaacaatgaaaaggcccccaaggtagttatccttaaaaaagccacagcatacatcctgtccgtccaagcagaggagcaaaagctcatttctgaagaggacttgttgcggaaacgacgagaacagttgaaacacaaacttgaacagctacggaactcttgtgcgtaaggaaaagtaaggaaaacgattccttctaacagaaatgtcctgagcaatcacctatgaacttgtttcaaatgcatgatcaaatgcaacctcacaaccttggctgagtc  31 202504ggaaacctctcagtgtcttgacatcaccctacccaggcggtgggtctccaccacagccactttgagtctgtggtccctgg_atagggtggcttctcctgactggcaggatgaccttagccaagatattcctctgttccctctgctgagataaagaattcccttaacatgatataatccacccatgcaaatagctactggcccagctaccatttaccatttgcctacagaatttcattcagtctacactttggcattctctctggcgatggagtgtggctgggctgaccgcaaaaggtgccttacacactgcccccaccctcagccgttgccccatcagaggctgcctcctccttctgattaccccccatgttgcatatcaggg  32 202718atccccaactgtgacaagcatggcctgtacaacctcaaacagtgcaagatgtctctgaacgggcagcgtggggagtgct_atggtgtgtgaaccccaacaccgggaagctgatccagggagcccccaccatccggggggaccccgagtgtcatctcttctacaatgagcagcaggaggcttgcggggtgcacacccagcggatgcagtagaccgcagccagccggtgcctggcgcccctgccccccgcccctctccaaacaccggcagaaaacggagagtgcttgggtggtg  33 202779ccgaacgtgggcgccaatggcgagatctgcgtcaacgtgctcaagagggactggacggctgagctgggcatccgac_s_atacgtactgctgaccatcaagtgcctgctgatccaccctaaccccgagtctgcactcaacgaggaggcgggccgcctgctcttggagaactacgaggagtatgcggctcgggcccgtctgctcacagagatccacgg  34 202831ctacccttatgatgacccattttccctcatgaccgatcccaagctcatcatttggagccctgtgcgccgctcagatgtggcc_attggaactttgagaagttcctcatagggccggagggagagcccttccgacgctacagccgcaccttcccaaccatcaacattgagcctgacatcaagcgcctccttaaagttgccatatagatgtgaactgctcaacacacagatctcctactccatccagtcctgaggagccttaggatgcagcatgccttcaggagacactgctggacctcagcattcccttgatatcagtccccttcactgcagagccttgcctttcccctctgcctgtttccttttcctctcccaaccctctggttggtgattcaacttgggctccaagacttgggtaagctctgggccttcacagaatgatggcaccacctaaaccctcatgggtgg  35 202833gaagcgtttaggcatgtttaacatccagcactgtaagaagctgtccagctgggtactgctaatgaaatacctgggcaatgc_s_atcaccgccatcttcttcctacctgatgaggggaaactacagcacctggaaaatgaactcacccacgatatcatcaccaagttcctggaaaatgaagacagaaggtctgccagcttacatttacccaaactgtccattactggaa  36202859gtacccagttaaattttcatttcagataaacaacaaataattttttagtataagtacattattgtttatctgaaagttttaattgaac_x_attaacaatcctagtttgatactcccagtcttgtcattgccagctgtgttggtagtgctgtgttgaattacggaataatgagttagaactattaaaacagccaaaactccacagtcaatattagtaatttcttgctggagaaacttgtttattatgtacaaatagattcttataatattatttaaatgactgcatttttaaatacaaggctttattttttttaactttaagatgtttttatgtgctctccaaattttttttactgtttctgattgtat  37 202935gagaggaccaaccagaattccctttggacatttgtgtttttttgtttttttttttttgttttgttttttcttcttcttcttcttccttaaaga_s_atcatttaagctaaaggcaactcgtacccaaatttccaagacacaaacatgacctatccaagcgcattacccacttgtggccaatcagtggccaggccaaccttggctaaatggagcagcgaaatcaacgagaaactggactttttaaaccctcttcagagcaagcgtggaggatgatggagaatcgtgtgatcagtgtgctaaatctctctgcctgtttggactttgtaattatttttttagcagtaattaaagaaaaaagtcctctgtgaggaatattctctattttaaatatttttagtatgtactgtgtatgattcattaccattttgaggggatttatacatattttagataaaattaaatgctcttatttttccaacagctaaactactcttagttgaacagtgtgccctagcttttcttgcaaccagagta  38 202936gtagtgtatcactgagtcatttgcagtgttttctgccacagacctttgggctgccttatattgtgtgtgtgtgtgggtgtgtgtg_s_attgttttgacacaaaaacaatgcaagcatgtgtcatccatatttctctacatcttctcttggagtgagggaggctacctggaggggatcagcccactgacagaccttaatcttaattactgctgtggctagagagtttgaggattgctttttaaaaaagacagcaaacttttttttttatttaaaaaaagatatattaacagttttagaagtcagtagaataaaatcttaaagcactcataatatggcatccttcaatttctgtataaaagcagatctttttaaaaaagatacttctgtaacttaagaaacctggcatttaaatcatattttgtctttaggtaaaagctttggtttgtgttcgtgttttgtttgtttcacttgtttccctcccagccccaaaccttttgactctccgtgaaacttaccttt  39 202954gccttccctgaatcagacaaccttttcaaatgggtagggaccatccatggagcagctggaacagtatatgaagacctgag_atgtataagctctcgctagagttccccagtggctacccttacaatgcgcccacagtgaagttcctcacgccctgctatcaccccaacgtggacacccagggtaacatatgcctggacatcctgaaggaaaagtggtctgccctgtatgatgtcaggaccattctgctctccatccagagccttctaggagaacccaacattgatagtcccttgaacacacatgctgccgagctctggaaaaaccccacagcttttaagaagtacctgcaagaaacctactcaaagcaggtcaccagccaggagccctgacccaggctgcccagcctgtccttgtgtcgtctttttaatttttccttagatggtctgtcctttttgtgattt  40 202998gccagtcttgaccgggatgaggcccacagacaggttgtcatcagcttgtcccattcaagccaccgagctcaccacagac_s_atacagtggagccgcgctcttctccagtgacacgtggacaaatgcgggctcatcagcccccccagagagggtcaggccgaaccccatttctcctcctcttaggtcattttcagcaaacttgaatatctagacctctcttccaatgaaaccctccagtctattatagtcacatagataatggtgccacgtgttttctgatttggtgagctcagacttggtgcttccctctccacaacccccaccccttgtttttcaagatactattattatattttcacagacttttgaagcacaaatttattggcatttaatattggacatctgggcccttggaagtacaaatctaaggaaaaaccaacccactgtgtaagtgactcatcttcctgttgttccaattctgtgggtttttgattcaacggtgctataaccagggtcctgggtgacagggcgctcactgagcaccatgtgtcatcacagaca  41 203083caggaaatagtcactcatcccactccacataaggggtttagtaagagaagtctgtctgtctgatgatggatagggggcaa_atatctttttcccctttctgttaatagtcatcacatttctatgccaaacaggaacgatccataactttagtcttaatgtacacattgcattttgataaaattaattttgttgtttcctttgaggttgatcgttgtgttgttttgctgcactttttacttttttgcgtgtggagctgtattcccgagacaacgaagcgttgggatacttcattaaatgtagcgactgtcaacagcgtgcaggttttctgtttctgtgttgtggggtcaaccgtacaatggtgtgggaatgacgatgatgtgaatatttagaatgtaccatattttttgtaaattatttatgtttttctaaacaaatttatcgtataggagatgaaacgtcatgtgttttgccaaagactgtaaatatttatttatgtgttcacatggtcaaaatttcaccactgaaaccctgcacttagctagaacct  42 203124atggtaacatgtatctttgccctgggtctgggtgggtccagtcagtctcagatttacaagcatttaggagcctaggtaaaag_s_atctgctagtattcttttaaaagttatatttatgacttgcaatgatagaaaactccttccaattaaatggcattttataatattatgtgtgtacttcacagtgttaaaaataccctcatacgttattgcatttgatatcacagaaagtgcattttaaccagtactctgggtgcaataaataatatgtagaaatttaagtcctccaattccagcatatccagtgagttttgacagtgtgtttatgtggaatgtttaaggatatacaattgtactttatataaattggttcttgttcttcttaaatgtgacatgaaataattgtgctgctacattatactggaaattaacaggggaaaagggaagagctcttggctcccttgaggttctgctagtggtgttaggagtggttacaactgagcttttagtaaccatttaaccg  43 203213tgctaagttcaagtttcgtaatgctttgaagtatttttatgctctgaatgtttaaatgttctcatcagtttcttgccatgttgttaact_atatacaacctggctaaagatgaatatttttctactggtattttaatttttgacctaaatgtttaagcattcggaatgagaaaactatacagatttgagaaatgatgctaaatttataggagttttcagtaacttaaaaagctaacatgagagcatgccaaaatttgctaagtcttacaaagatcaagggctgtccgcaacagggaagaacagttttgaaaatttatgaactatcttatttttaggtaggttttgaaagctttttgtctaagtgaattcttatgccaggtcagagtaataactgaaggagntgcttatcttggctttcgagtctgagtttaaaactacacattttgacatagtgtttattagcagccatc  44 203256gtggccgtagcaacttggcggagacaggctatgagtctgacgttagagtggttgcttccttagccatcaggatggagga_atatgtgggcagtttgacttcagcactgaaaacctctccacctgggccagggttgcctcagaggccaagtttccagaagcctcttacctgccgtaaaatgctcaaccctgtgtcctgggcctgggcctgctgtgactgacctacagtggactttctctctggaatggaaccttcttaggcctcctggtgcaacttaatttttttttttaatgctatcttcaaaacgttagagaaagttcttcaaaagtgcagcccagagctgctgggcccactggccgtcctgcatttctggtttccagaccccaatgcctcccattcggatggatctctgcgtttttatactgagtgtgcctaggttgccccttattttttattttccctgttgcgttgctatagatg  45203313agagtggtcttttcaacactcctccccctactccaccggacctcaaccaggacttcagtggatttcagcttctagtggatgtt_s_atgcactcaaacgggctgcagagatggagcttcaggcaaaacttacagcttaacccattttcaagcaaaacagttctcagaaatgtcatgattgccggggtgaaggcaagagatgaattgcattattttatatattttttattaatatttgcacatgggattgctaaaacagcttcctgttactgagatgtcttcaatggaatacagtcattccaagaactataaacttaaagctactgtagaaacaaagggttttcttttttaaatgtttcttggtagattattcataatgtgagatggttcccaatatcatgtgatttttttttttcctccccttccctttttttgttattttttcagactgtgcaatacttagagaacctatagcatcttctcattcccatgtggaacaggatgcccacatactgtctaatta  46 203510gaagccaagggttaacccagcaagctacaaagagggtgtgtcacactgaaactcaatagttgagtttggctgttgttgca_atggaaaatgattataactaaaagctctctgatagtgcagagacttaccagaagacacaaggaattgtactgaagagctattacaatccaaatattgccgtttcataaatgtaataagtaatactaattcacagagtattgtaaatggtggatgacaaaagaaaatctgctctgtggaaagaaagaactgtctctaccagggtcaagagcatgaacgcatcaatagaaagaactcggggaaacatcccatcaacaggactacacacttgtatatacattcttgagaacactgcaatgtgaaaatcacgtttgctatttataaacttgtccttagattaatgtgtctggacagattgtgggagtaagtgattcttctaagaattagatacttgtcactgcctatacctgcagctgaactgaatggtacttcgtatg  47 203860gaagcaggtggaaacatgagcattcagtttcttggtacagtgtacaaggtgaatatcttaaccagacttgccgcagaattg_ataacaaatttatgctggaaaaagtgactgaggacacaagcagtgttctgcgttccccgatgcccggagtggtggtggccgtctctgtcaagcctggagacgcggtagcagaaggtcaagaaatttgtgtgattgaagccatgaaaatgcagaatagtatgacagctgggaaaactggcacggtgaaatctgtgcactgtcaagctggagacacagttggagaaggggatctgctcgtggagctggaatgaaggatttataacctttcagtcatcacccaatttaattagccatttgcatgatgctttcacacacaattgattcaagcattatacaggaacacccctgtgcagctacgtttacgtcgtcatttattccacagagtcaagaccaatattctgccaaaaaatcaccaatggaaattttcatgatataaatacttgtactatagatgtacttctgctgtg  48 203878tgccagcgactgtctcagactgggcagggaggctttggcatgacttaagaggaagggcagtcttgggacccgctatgc_s_ataggtcctggcaaacctggctgccctgtctcatccctgtccctcagggtagcaccatggcaggactgggggaactggagtgtccttgctgtatccctgttgtgaggttccttccaggggctggcactgaagcaagggtgctggggccccatggccttcagccctggctgagcaactgggctgtagggcagggccacttcctgaggtcaggtcttggtaggtgcctgcatctgtctgccttctggctgacaatcctggaaatctgttctccagaatccaggccaaaaagttcacagtcaaatggggaggggtattcttcatgcaggagaccccaggccctggaggctgcaacatacctcaatcctgtcccaggccggatcctcctgaagcccctttcgcagcactgctatcctccaaagccattgtaaatgtgtgtacagtgtgtataaaccttcttcttctt  49203895gactaatccatacacagttaacctaatgccaaataaatactggttaaataaatgtatggcacagaatataatttgactatcaa_atgacttttagcataatgaaaaaccctctctctatatatatatgtgtatatgaattatgtgggcattcttgatacttcaagttctagtttgaaaaaaatacataactaatttaattttacacaaaaatatttatgcagattttcagaatttcatatcaggaaatgacccttttatgtctgttaaatatcaaaacaatttgctacagtgttaatctgcatggtctttaagcctgctgtagttgagttgcagacagtgcatgaaaaagtattccgctgggaattgagccatgccaccaaagccaagaggagcgcatggaaacccggtagtctagaactaatcagattactgattttagggcacagcaccagatgaattgttgtatatgcttgtaaaaattgattctgtgtgttcctctgaacaaagcgg  50 203896gtccagcttgaacatctagaattcctagagaaacagaatgagcaggcgaaggagatgcagcagatggtgaaattggaa_s_atgccgagatggaccgcagaccagcaacagtagtatgaaactccaaaatgcaaactgaagcagcaaacccacaaagcatcaaaagactcactcacaaaacactgaacacaaactccatggatgaaagctgtttattttgtttcctttatgtgtaaacaagatgatatctgaaaccagagagacttggaatgtctgactgacttctatttaacagcttgagtattgcatttccttggccaaacaaaaatagctacaaatccacaaaaatttactattccagtaaggcagagtccaaccattgataatacaacttaaacatgtttgctataaaataccatcacaagtaaatgagcttggtgtgaacaactcttcctttgtgatgccttagg  51 203961ggactagagcaacatcgtgctgcccaaaggactaacctatgcaaactagttcacattttagtggatgtcgcagttaatgtgt_ataataagacattatttcccctgcataatgtacaacagcattgaaatgacacattaagcctagcatcacattgtatagtacagtcactcacaaacccttcaaggctaccctaatcattaacattaatatttgtttaaaagcaaatcaccgatttatctattgaaactacttaaatgacggcaaaccaggaatgacagatggctgtgtcagcaatggctttaatgtgttccctgcaagtggtctcctatgantagaactgcgttctcaaatgcactctcttcagggtcttaatattctgtgttttctctctgtatttgtaaaacattataacacattaatttcctatctctacacatttgg  52 203962gtcaaggcattgtatgttgcttctgtggttattattctgtgatgcttagactacttgaacccataaacttggaagaatctttgag_s_atcaaattttctcagttgtctgtatgacttcagtatattcctgggaatgccataggattttttgtgcttgatacatggtatccagtttgcatagtatcacttctttgtaatccagttgctgttaagaatgatgtactttaaaggaaaagagaaaactgcatcacagtcccattctccagtgtccatgcaatgaattgctgagcatttaggaagcagcaccaagtctattacaggcatggtgtgaaacttgatgtttgacctgtgatcaaaattgaaccattgtacagtttggcttctgtttgcttcaaaatatgtagaattgtggttgatgattaatttgcgagactaactttgagagtgtaacagttttgaagaaaacattgaatgttttacaaatgaaggggcttcacggaatgttacaa 53 204051aaccagccagtcccaagaagaacattaaaactaggagtgcccagaagagaacaaacccgaaaagagtgtgagctaac_s_attagtttccaaagcggagacttccgacttccttacaggatgaggctgggcattgcctgggacagcctatgtaaggccatgtgccccttgccctaacaactcactgcagtgctcttcatagacacatcttgcagcatttttcttaaggctatgcttcagtttttctttgtaagccatcacaagccatagtggtaggtttgccctttggtacagaag  54 204127ttgtgttttgtcattagctctgccctttttaattaaatattttggttcatggaccaaagggtttacttgacaaatttgtgtgacaga_atctccgaacaattcctttactacgaagtataatttataaaataaaatatacccattttaagggtacagtttgatttttgaccagtgaaactatgatcccaatcaaggtatagatgccgtcaccccaaaaagttccctccatatccctttgcagtcagttcatccctaccctggcccagatgatcactgatcttgtcattatagatgagttttgccagttcaagaatttaatggaatcagatattgtaagcattcttgtgtaatacttcattctctctcattattgagattcatccatattgttgaatgtttcactagttaatgtttattgttcaatatttttgtatatacttttaaagcctattcacttgctgatggatctt  55 204170cgctctcgtttcattttctgcagcgcgccacgaggatggcccacaagcagatctactactcggacaagtacttcgacgaa_s_atcactacgagtaccggcatgttatgttacccagagaactttccaaacaagtacctaaaactcatctgatgtctgaagaggagtggaggagacttggtgtccaacagagtctaggctgggttcattacatgattcatgagccagaaccacatattcttctctttagacgacctcttccaaaagatcaacaaaaatgaagtttatctggggatcgtcaaatctttttcaaatttaatgtatatgtgtatataaggtagtattcagtgaatacttgagaaatgtacaaatattctttccatacctgtgcatgagctgtattcttcacagcaacagagctcagttaaatgcaactgcaagtaggttactgtaagatgtttaagataaaagttcttccagtcagtttttctcttaagtgcct 56 204259ctcatggggactcctacccatttgatgggccaggaaacacgctggctcatgcctttgcgcctgggacaggtctcggagg_atagatgctcacttcgatgaggatgaacgctggacggatggtagcagtctagggattaacttcctgtatgctgcaactcatgaacttggccattctttgggtatgggacattcctctgatcctaatgcagtgatgtatccaacctatggaaatggagatccccaaaattttaaactttcccaggatgatattaaaggcattcagaaactatatggaaagagaagtaattcaagaaagaaatagaaacttcaggcagaacatccattcattcattcattggattgtatatcattgttgcacaatcagaattgataagcactgttcctccactccatttagcaattatgtcacccttttttattgcagttggtttttgaatgtctttcactccttttattggttaaactcctttatggtgtgactgtgtcttattccatctatgagctttgtcagtgcgcgtagatgt  57 204320gaaaatgtaccttggtgccaccaacccattttgtgccacatgcaagttttgaataaggatgtatggaaaacaacgctgcat_atatacaggtaccatttaggaaataccgatgcctttgtgggggcagaatcacagacaaaagctttgaaaatcataaagatataagttggtgtggctaagatggaaacagggctgattcttgattcccaattctcaactctccttttcctatttgaatttctttggtgctgtagaaaacaaaaaaagaaaaatatatattcataaaaaatatggtgctcattctcatccatccaggatgtactaaaacagtgtgtttaataaattgtaattattttgtgtacagttctatactgttatctgtgtccatttccaaaacttgcacgtgtccctgaattccgctgactctaatttatgaggatgccgaactctgatggcaataatatatgtattatgaaaatgaagttatgatttccgatgaccctaagtcc  58 204351gggtctgaatctagcaccatgacggaactagagacagccatgggcatgatcatagacgtcttttcccgatattcgggcag_atcgagggcagcacgcagaccctgaccaagggggagctcaaggtgctgatggagaaggagctaccaggcttcctgcagagtggaaaagacaaggatgccgtggataaattgctcaaggacctggacgccaatggagatgcccaggtggacttcagtgagttcatcgtgttcgtggctgcaatcacgtctgcctgtcacaagtactttgagaaggcaggactcaaatgatgccctggagatgtcacagattcctgcagagccatggtcccaggcttcccaaaagtgtttgttggcaattattcccctaggctgagcctgctcatgtacc  59 204401gtagctggacccacgaggaggaaccaggctactttccccagtactgaggtggtggacatcgtctctgccactcctgacc_atcagccctgaacaaagcacctcaagtgcaaggaccaaagggggccctggcttggagtgggttggcttgctgatggctgctggaggggacgctggctaaagtgggtaggccttggcccacctgaggccccaggtgggaacatggtcacccccactctgcataccctcatcaaaaacactctcactatgctgctatggacgacctccagctctcagttacaagtgcaggcgactggaggcaggactcctgggtccctgggaaagagggtactaggggcccggatccaggattctgggaggcttcagttaccgctggccgagctgaagaactgggtatgaggctggggcggggctggaggtggcgccccctggtgggacaacaaagaggacaccatttttccagagctgc  60 204404agaccaagacataccggcagatcaggttaaatgagttattaaaggaacattcaagcacagctaatattattgtcatgagtct_atcccagttgcacgaaaaggtgctgtgtctagtgctctctacatggcatggttagaagctctatctaaggacctaccaccaatcctcctagttcgtgggaatcatcagagtgtccttaccactattcataaatgttctatacagtggacagccctccagaatggtacttcagtgcctagtgtagtaacctgaaatcttcaatgacacattaacatcacaatggcgaatggtgacttttctttcacgatttcattaatttgaaagcacacaggaaagcttgctccattgataacgtgtatggagacttcggttttagtcaattccatatc 61 204470tatgattaactctacctgcacactgtcctattatattcattctttttgaaatgtcaaccccaagttagttcaatctggattcatattt_ataatttgaaggtagaatgttttcaaatgttctccagtcattatgttaatatttctgaggagcctgcaacatgccagccactgtgatagaggctggcggatccaagcaaatggccaatgagatcattgtgaaggcaggggaatgtatgtgcacatctgttttgtaactgtttagatgaatgtcagttgttatttattgaaatgatttcacagtgtgtggtcaacatttctcatgttgaaactttaagaactaaaatgttctaaatatcccttggacattttatgtctttcttgtaaggcatactgccttgtttaatggtagttttacagtgtttctggcttagaaca  62 204475gaagaactgtctattttctcagtcatttttaacctctagagtcactgatacacagaatataatcttatttatacctcagtttgcata_attttttttactatttagaatgtagccctttagtactgatataatttagttccacaaatggtgggtacaaaaagtcaagtttgtggcttatggattcatataggccagagttgcaaagatcttttccagagtatgcaactctgacgttgatcccagagagcagcttcagtgacaaacatatcctttcaagacagaaagagacaggagacatgagtctttgccggaggaaaagcagctcaagaacacatgtgcagtcactggtgtcaccctggataggcaagggataactcttctaacaca  63 204580agatgatggaccctggttatcccaaactgattaccaagaacttccaaggaatcgggcctaaaattgatgcagtcttctattc_attaaaaacaaatactactatttcttccaaggatctaaccaatttgaatatgacttcctactccaacgtatcaccaaaacactgaaaagcaatagctggtttggttgttagaaatggtgtaattaatggtttttgttagttcacttcagcttaataagtatttattgcatatttgctatgtcctcagtgtaccactacttagagatatgtatcataaaaataaaatctgtaaaccataggtaatgattatataaaatacataatatttttcaattttgaaaactctaattgtccattcttgcttgactctactattaagtttgaaaatagttaccttcaaagcaagataattctatttgaagcatgctctgtaagttgcttcctaacatccttggactgagaaattatacttacttctggcataactaaa 64 204620tgccgtgctcccaaaacattttaaatgaaagtattggcattcaaaaagacagcagacaaaatgaaagaaaatgagagca_s_atgaaagtaagcatttccagcctatctaatttctttagttttctatttgcctccagtgcagtccatttcctaatgtataccagcctactgtactatttaaaatgctcaatttcagcaccgatggccatgtaaataagatgatttaatgttgattttaatcctgtatataaaataaaaagtcacaatgagtttgggcatatttaatgatgattatggagccttagaggtctttaatcattggttcggctgcttttatgtagtttaggctggaaatggtttcacttgctctttgactgtcagcaagactgaagatggcttttcctggacagctagaaaacacaaaatcttgtaggtcattgcacctatctcagccataggtgcagtttgcttctacatgatgctaaaggctgcgaatgggatcctgatggaactaaggactccaatgtcgaactcttctttgctgc  65 204702tgctctccagtgtacccatgatggaagtatcttgatagtacccaaagaactggtggcctcaggccacaaaaaggaaacc_s_atcaaaagggaaagagaaagtgagaagaaactgaagatggactctattatgtgaagtagtaatgttcagaaactgattatttggatcagaaaccattgaaactgcttcaagaattgtatctttaagtactgctacttgaataactcagttaacgctgttttgaagcttacatggacaaatgtttaggacttcaagatcacacttgtgggcaatctgggggagccacaacttttcatgaagtgcattgtatacaaaattcatagttatgtccaaagaataggttaacatgaaaacccagtaagactttccatcttggcagccatcctttttaagagtaagttggttacttcaaaaagagcaaacactggggatcaaattattttaagaggtatttcagttttaaatgcaaaatagccttattttcatttagtttgttagcactatagtgagcttttcaaacactattttaatc  66 204855cttcgttcgcagagcttttcagattgtggaatgttggataaggaattatagacctctagtagctgaaatgcaagaccccaag_ataggaagttcagatcttaatataaattcactttcatttttgatagctgtcccatctggtcatgtggttggcactagactggtggcaggggcttctagctgactcgcacagggattctcacaatagccgatatcagaatttgtgttgaaggaacttgtctcttcatctaatatgatagcgggaaaaggagaggaaactactgcctttagaaaatataagtaaagtgattaaagtgctcacgttaccttgacacatagtttttcagtctatgggtttagttactttagatggcaagcatgtaacttatattaatagtaatttgtaaagttgggtggataagctatccctgttgccggttcatggattacactctataaaaaatatatatttaccaaaaaattttgtgacattcatctcccatctcttccttgacatgcattgtaaataggttcttcttgttctgag  67 204885tttccagaacatgaacgggtccgaatacttcgtgaagatccagtccttcctgggtggggcccccacggaggatttgaag_s_atgcgctcagtcagcagaatgtgagcatggacttggccacgttcatgaagctgcggacggatgcggtgctgccgttgactgtggctgaggt  68 205174gtctggcacaccatggatgacaatgaagaaaatttggatgaatcaaccattgacaatctaaacaaaatcctacaagtcttt_s_atgtgttggaatatcttcatttgtaatactctgatttagtttaggataattggttctagaattgaattcaaaagtcaaggcatcatttaaaataatctgatttcagacaaatgctgtgtggaaacatctatcctatagatcatcctattcttatgtgtctttggttatcagatcaattacagaataattgtgttgtgatattgtgtcctaaattgctcattaatttttatttacagattgaaaaagaggcaccgtgtaaagaaaatggcaaaataaatatctttccaaggatcatcatcacgatagctaaacagtacttaaatagcggttggaactaggtagcctttcgaattttatgattttttcatatgtggaaatctattacatgtaatacaaaacaaacatgtagtttgaaggcggtcagatttctttgag  69 205361aaggcggctgcagaagatgtcaatgttactttcgaagatcaacaaaagataaacaaatttgcacggaatacaagtagaat_s_atcacagagctgaaggaagaaatagaagtaaaaaagaaacaactccaaaacctagaagatgcttgtgatgacatcatgcttgcagatgatgattgcttaatgataccttatcaaattggtgatgtcttcattagccattctcaagaagaaacgcaagaaatgttagaagaagcaaagaaaaatttgcaagaagaaattgacgccttagaatccagagtggaatcaattcagcgagtgttagcagatttgaaagttcagttgtatgcaaaattcgggagcaacataaaccttgaagctg  70 205366cctcagcctgatcaggcttcctggtgagaactgaggagcggactcacttgatgtttcctggaagcagagcaaaagttctc_s_atttgtccctgtcgcgtctcattttgtccatgtcccccgtgcacggttcaatggtagattcgctgtcctcagcgggggccttgaagactccctgatcccagacctggtcgtctctcccaccccctccccaaagccactggaaggagcacatactacctagaagtaagaagaggagcctcagaagaaaacaaagttctattttattaattttctatgtgttgtgtttgtagtcttgtcttagctctggacg  71 205470gccaacatcaccatcattgagcaccagaagtgtgagaacgcctaccccggcaacatcacagacaccatggtgtgtgcc_s_atagcgtgcaggaagggggcaaggactcctgccagggtgactccgggggccctctggtctgtaaccagtctcttcaaggcattatctcctggggccaggatccgtgtgcgatcacccgaaagcctggtgtctacacgaaagtctgcaaatatgtggactggatccaggagacgatgaagaacaattagactggacccacccaccacagcccatcaccctccatttccacttggtgtttggttcctgttcactctgttaataagaaaccctaagccaagaccctctacgaacattctttgggcctcctggactacaggagatgctgtcacttaataatcaacctggggttcgaaatcagtgagacctggattcaaattctgccttgaaatattgtgactctgggaatgacaacacctggtttgttctctgttgtatccccagccccaaagacagctcctggccatatatca  72205476ttcacacggcagctggccaatgaaggctgtgacatcaatgctatcatctttcacacaaagaaaaagttgtctgtgtgcgca_ataatccaaaacagacttgggtgaaatatattgtgcgtctcctcagtaaaaaagtcaagaacatgtaaaaactgtggcttttctggaatggaattggacatagcccaagaacagaaagaaccttgctggggttggaggtttcacttgcacatcatggagggtttagtgcttatctaatttgtgcctcactggacttgtccaattaatgaagttgattcatattgcatcatagtttgctttgtttaagcatcacattaaagttaaactgtattttatgttatttatagctgtaggttttctgtgtttagctatttaatactaattttccataagctattttggtttagtgcaaagtataaaattatatttgggggggaataagattatatggactttcttgcaagcaacaa  73205479cccgaccggtgggcatttgtgaggcccatggttgagaaatgaataatttcccaattaggaagtgtaagcagctgaggtct_s_atcttgagggagcttagccaatgtgggagcagcggtttggggagcagagacactaacgacttcagggcagggctctgatattccatgaatgtatcaggaaatatatatgtgtgtgtatgtttgcacacttgttgtgtgggctgtgagtgtaagtgtgagtaagagctggtgtctgattgttaagtctaaatatttccttaaactgtgtggactgtgatgccacacagagtggtctttctggagaggttataggtcactcctggggcctcttgggtcccccacgtgacagtgcctgggaatgtacttattctgcagcatgacctgtgaccagcactgtctcagtttcactttcacatagatgtccctttcttggccagttatcccttccttttagcctagttcatccaatcctcactgggtgggg  74 205513aacaaagactcttcttgcgtctctgcttcttggtaacttcaacatctccgctgatgagcctataactgtgacacctcctgactc_atacaatcatatatctccgtcaattactctgtgagaatcaatgaaacatatttcaccaatgtcactgtgctaaatggttctgtcttcctcagtgtgatggagaaagcccagaaaatgaatgatactatatttggtttcacaatggaggagcgctcatgggggccctatatcacctgtattcagggcctatgtgccaacaataatgacagaacctactgggaacttctgagtggaggcgaaccactgagccaaggagctggtagttacgttgtccgcaatggagaaaacttggaggttcgctggagcaaatactaataagcccaaactttcctcagctgcataaaatccatttgcagtggagttccatgtttattgtccttatgccttct  75205713caaacgtattggcaggcgaaccccttccgtgctgtggccgagcctggcatccaactcaaggctgtgaagtcttccacag_s_atgccccggggaacagctgcggaacgctctgtggcatacaggagacacagagtcccaggtgcggctgctgtggaaggacccgcgaaacgtgggttggaaggacaagaagtcctatcgttggttcctgcagcaccggccccaagtgggctacatcagggtgcgattctatgagggccctgagctggtggccgacagcaacgtggtcttggacacaaccatgcggggtggccgcctgggggtcttctgcttctcccaggagaacatcatctgggccaacctgcgttaccgctgcaatgacaccatcccagaggactatgagacccatcagctgcggcaagcctagggacc  76 205765caccacctacctatgatgccgtggtacagatggagtaccttgacatggtggtgaatgaaacactcagattattcccagttg_atctattagacttgagaggacttgcaagaaagatgttgaaatcaatggggtattcattcccaaagggtcaatggtggtgattccaacttatgctcttcaccatgacccaaagtactggacagagcctgaggagttccgccctgaaaggttcagtaagaagaaggacagcatagatccttacatatacacaccctttggaactggacccagaaactgcattggcatgaggtttgctctcatgaacatgaaacttgctctaatcagagtccttcagaacttctccttcaaaccttgtaaagaaacacagatccccttgaaattagacacgcaaggacttcttcaaccagaaaaacccattgttctaaaggtggattcaagagatggaaccctaagtggagaatgagttattctaaggacttctactttggtcttcaagaaagctgtgccccagaacaccagagatttcaacttagtca 77 205815tgctatgccttgtttttgtcaccaaaatcctggacagatgcagatctggcctgccagaagcggccctctggaaacctggtg_attctgtgctcagtggggctgagggatccttcgtgtcctccctggtgaagagcattggtaacagctactcatacgtctggattgggctccatgaccccacacagggcaccgagcccaatggagaaggttgggagtggagtagcagtgatgtgatgaattactttgcatgggagagaaatccctccaccatctcaagccccggccactgtgcgagcctgtcgagaagcacagcatttctgaggtggaaagattataactgtaatgtgaggttaccctatgtctgcaagttcactgactagtgcaggagggaagtcagcagcctgtgtttggtgtgcaactcatcatgggcatgagaccagtgtgaggactcaccctggaagagaatattcgcttaattcccccaacctgaccacctcattcttatctttcttctgtttcttcctccccgctgtcatttcagtctcttcattttgtc 78 205825tttccattcccaatctagtgctagatgtataaatctttcttttgattcttcctaacaaaatattttctgggttaaaaccccagccaa_atctcattgggttgtagccaaaggttcactctcaagaagctttaatatttaaataaaatcatattgaatgtttccaacctggagtataatattcagatataaaacagttttgtcagtctttcttagtgcctgtgtggatttttgtgaaaatgtcaaagagaaaacttatatactatttcccttgaaattttaaactatattttctttacaggtatttataatataccaatgcttttatcaaacagaattttaaagagcataataaattatattaaagaaccaaaagttttcctgagaataagaaagtttcacccaataaaatatttttgaaaggcatgttcctctgtcaatgaaaaaaagtacatgtatgtgttgtgatattaaaagtgacatttgtctaatagcctaatacaacatgtagctgagtttaacatgtgtggtcttg  79 205828gaaaatcgatgcagccatttctgataaggaaaagaacaaaacatatttctttgtagaggacaaatactggagatttgatga_atgaagagaaattccatggagccaggctttcccaagcaaatagctgaagactttccagggattgactcaaagattgatgctgtttttgaagaatttgggttcttttatttctttactggatcttcacagttggagtttgacccaaatgcaaagaaagtgacacacactttgaagagtaacagctggcttaattgttgaaagagatatgtagaaggcacaatatgggcactttaaatgaagctaataattcttcacctaagtctctgtgaattgaaatgttcgttttctcctgcctgtgctgtgactcgagtcacactcaagggaacttgagcgtgaatctgtatcttgccggtcatttttatgttattacagggcattcaaatgggctgctgcttagcttgcaccttgtcacatagagtgatctttcccaagagaaggggaagcactcgtgtgcaacagac  80 205886cacccaggcggagggtgccttcgtggcctcactgattaaggagagtagcactgatgacagcaatgtctggattggcctc_atcatgacccaaaaaagaaccgccgctggcactggagtagtgggtccctggtctcctacaagtcctgggacactggatccccgagcagtgctaatgctggctactgtgcaagcctgacttcatgctcaggattcaagaaatggaaggatgaatcttgtgagaagaagttctcctttgtttgcaagttcaaaaactagaggaagctgaaaaatggatgtctagaactggtcctgcaattactatgaagtcaaaaattaaactagactatgtctccaactcagttcagaccatctcctccctaatgagtttgcatcgctgatcttcagtaccttc  81 205890gatcttaaagccacggagaagcctctcatcttatggcattgacaaagagaagaccatccaccttaccctgaaagtggtga_s_atagcccagtgatgaggagctgcccttgtttcttgtggagtcaggtgatgaggcaaagaggcacctcctccaggtgcgaaggtccagctcagtggcacaagtgaaagcaatgatcgagactaagacgggtataatccctgagacccagattgtgacttgcaatggaaagagactggaagatgggaagatgatggcagattacggcatcagaaagggcaacttactcttcctggcatcttattgtattggagggtgaccaccctggggatggggtgttggcaggggtcaaaaagcttatttcttttaatctcttactcaacgaacacatcttctgatgatttcccaaaattaatgagaatgagatgagtagagtaagatttgggtgggatgggtaggatgaagtatattgcccaactctatgtttctttga  82 205910gactccaaggaagctcagatgcctgcagtcattaggttttagcgtcccatgagccttggtatcaagaggccacaagagtg_s_at ggaccccaggggctc  83 205927tccacacacggccaggcctgtttatctacactgctgcccactcctctctccagctccacatgctgtacctggatcattctga_s_atagcaaattccgagcattacatcattttgtccataaatatttctaacatccttaaatatacaatcggaattcaagcatctcccattgtcccacaaatgtttggctgtttttgtagttggattgtttgtattaggattcaagcaaggcccatatattgcatttatttgaaatgtctgtaagtctctttccatctacagagtttagcacatttgaacgttgctggttgaaatcccgaggtgtcatttgacatggttctctgaacttatctttcctataaaatggtagttagatctggaggtctgattttgtggcaaaaatacttcctaggtggtgctgggtacttcttgttgcatcctgtcaggaggcagataatgctggtgcctctctattggtaatgttaagactgctgggtgggtttggagttcttggc  84 205941atactatttttcataccacgtgcatgtgaaagggactcatgtttgggtaggcctgtataagaatggcacccctgtaatgtaca_s_atcctatgatgaatacaccaaaggctacctggatcaggcttcagggagtgccatcatcgatctcacagaaaatgaccaggtgtggctccagcttcccaatgccgagtcaaatggcctatactcctctgagtatgtccactcctctttctcaggattcctagtggctccaatgtgagtacaccccacagagctaatctaaatcttgtgctagaaaaagcattctctaactctaccccaccctacaaaatgcatatggaggtaggctgaaaagaatgtaatttttattttctgaaatacagatttgagctatcagaccaacaaaccttccccctgaaaagtgagcagcaacgtaaaaacgtatgtgaagcctctcttgaa  85 205983gccgaccatctggatcacatcaaggaggtggcaggagccagagccgtgggttttggtggggactttgatggtgttccaa_atgggtccctgaggggctggaggacgtctccaagtatccagacctgatcgctgagctgctcaggaggaactggacggaggcggaggtcaagggcgcactggctgacaacctgctgagggtcttcgaggctgtggaacaggccagcaacctcacacaggctcccgaggaggagcccatcccgctggaccagctgggtggctcctgcaggacccattacggctactcctctggggcttccagcctccatcgccactgggggctcctgctggcctccctcgctcccctggtcctctgtctgtctctcctgtgaaacctgggagaccagagtcccttttagggttcccggagctccgggaagacccgcccatcccaggactccagatgccaggagccctgctgcccacatgcaaggaccagcatctcctgagaggacgcctgggcttacctggggggcaggatgcctggggacagttcag  86 206224ggaggataggataatcccgggtggcatctataacgcagacctcaatgatgagtgggtacagcgtgcccttcacttcgcc_atatcagcgagtataacaaggccaccaaagatgactactacagacgtccgctgcgggtactaagagccaggcaacagaccgttgggggggtgaattacttcttcgacgtagaggtgggccgaaccatatgtaccaagtcccagcccaacttggacacctgtgccttccatgaacagccagaactgcagaagaaacagttgtgctctttcgagatctacgaagttccctgggagaacagaaggtccctggtgaaatccaggtgtcaagaatcctagggatctgtgccag  87 206239gagacgtggtaagtgcggtgcagttttcaactgacctctggacgcagaacttcagccatgaaggtaacaggcatctttctt_s_atctcagtgccttggccctgttgagtctatctggtaacactggagctgactccctgggaagagaggccaaatgttacaatgaacttaatggatgcaccaagatatatgaccctgtctgtgggactgatggaaatacttatcccaatgaatgcgtgttatgttttgaaggtcggaaacgccagacttctatcctcattcaaaaatctgggccttgctgagaaccaaggttttgaaatcccatcaggtcaccgc  88 206286gtggaccttagaatacagttttgagtagagttgatcaaaatcaattaaaatagtctctttaaaaggaaagaaaacatctttaa_s_atggggaggaaccagagtgctgaaggaatggaagtccatctgcgtgtgtgcagggagactgggtaggaaagaggaagcaaatagaagagagaggttgaaaaacaaaatgggttacttgattggtgattaggtggtggtagagaagcaagtaaaaaggctaaatggaagggcaagtttccatcatctatagaaagctatataagacaagaactcccttttttttcccaaaggcattataaaaagaatgaagcctccttagaaaaaaaattatacctcaatgtccccaacaagattgcttaataaattgtgtttcctccaagctattcaattcttttaactgttgtagaagacaaaatgttcacaatatatttagttgtaaaccaagtgatcaaactacatattgtaaagcccattttt  89 206976aagtctgtagtctttatgatcctaaaagggaaaattgccttggtaactttcagattcctgtggaattgtgaattcatactaagct_s_atttctgtgcagtctcaccatttgcatcactgaggatgaaactgacttttgtcttttggagaaaaaaaactgtactgttgttcaagagggctgtgattaaaatctttaagcatttgttcctgccaaggtagttttcttgcattttgctctccattcagcatgtgtgtgggtgtggatgtttataaacaagactaagtctgacttcataagggctttctaaaaccatttctgtccaagagaaaatgactttttgctttgatattaaaaattcaatgagtaaaacaaaagctagtcaaatgtgttagcagcatgcagaacaaaaactttaaactttctctctcactatacagtatattgtcaatgtgaaagtgtggaatggaagaaatgtcgatcctgttgtaactga  90207158gcaccctggtgtgactctagtgatctacgtagctcggcttttttggcacatggatcaacaaaatcggcaaggtctcaggga_atccttgttaacagtggagtaactattcagattatgagagcatcagagtattatcactgctggaggaattttgtcaactacccacctggggatgaagctcactggccacaatacccacctctgtggatgatgttgtacgcactggagctgcactgcataattctaagtcttccaccctgtttaaagatttcaagaagatggcaaaatcatcttacatttttcagacttcatcttcaaaactgccattaccaaacgattccgccacacatcatttagctacagggctgatacatccttctgtggcttggagatgaataggatgattccgtgtgtgtactgattcaagaacaagcaatgatgacccactaaagagtgaatgccatttagaatctagaaatgttcacaaggtaccccaaaactctgtagct  91 207173gaacatccaagtctttcttcttttttaagttgtcaaagaagcttccacaaaattagaaaggacaacagttctgagctgtaatttc_x_atgccttaaactctggacactctatatgtagtgcatttttaaacttgaaatatataatattcagccagcttaaacccatacaatgtatgtacaatacaatgtacaattatgtctcttgagcatcaatcttgttactgctgattcttgtaaatctttttgcttctactttcatcttaaactaatacgtgccagatataactgtcttgtttcagtgagagacgccctatttctatgtcatttttaatgtatctatttgtacaattttaaagttcttattttagtatacatataaatatcagtattctgacatgtaagaaaatgttacggcatcacacttatatttta 92 207457aaccgaatgcggtgctacaactgtggtggaagccccagcagttcttgcaaagaggccgtgaccacctgtggcgaggg_s_atcagaccccagccaggcctggaacagatcaagctacctggaaaccccccagtgaccttgattcaccaacatccagcctgcgtcgcagcccatcattgcaatcaagtggagacagagtcggtgggagacgtgacttatccagcccacagggactgctacctgggagacctgtgcaacagcgccgtggcaagccatgtggcccctgcaggcattttggctgcagcagctaccgccctgacctgtctcttgccaggactgtggagcggatagggggagtaggagtagagaagggaacaagggagcaagggaacaagggacatctgaacatct  93 207850agaacagcagctttctagggacagctggaaagggacttaatgtgtttgactatttcttacgagggttctacttatttatgtattt_atatttttgaaagcttgtattttaatattttacatgctgttatttaaagatgtgagtgtgtttcatcaaacatagctcagtcctgattatttaattggaatatgatgggttttaaatgtgtcattaaactaatatttagtgggagaccataatgtgtcagccaccttgataaatgacagggtggggaactggagggtngggggattgaaatgcaagcaattagtggatcactgttagggtaagggaatgtatgtacacatctattttttatacttttttttttaaaaaagaatgtcagttgttatttattcaaattatctcacattatgtgttcaacatttttatgctgaagtttcccttagacattttatgtcttgcttgtagggcataatgccttgtttaatgtccattctgcagcgttt 94 208079ccctcaatctagaacgctacacaagaaatattttgtttttactcagcaggtgtgccttaacctccctattcagaaagctccac_satatcaataaacatgacactctgaagtgaaagtagccacgagaattgtgctacttatactggaacataatctggaggcaaggttcgactgcagtcgaaccttgcctccagattatgaaccagtataagtagcacaattctcgtggctactttcacttcagagtgtcatgtttattgatgtggagctttctgaatagggaggttaaggcacacctgctgagtaaaacaaatatttcttgtgtagcgttcttaggaatctggtgtctgtccggccccggtaggcctgttgggtttctagtcctccttaccatcatctccatatgagagtgtgaaaataggaacacgtgctctacctccatttagggatttgcttgggatacagaagaggccatgtgtctcagagctgttaagggcttatttttttaaaacattggagtcatagcatgtgtgtaa  95 208712gttttgggtatgtttaatctgttatgtactagtgttctgtttgttattgttttgttaattacaccataatgctaatttaaagagactcc_ataaatctcaatgaagccagctcacagtgctgtgtgccccggtcatctagcaagctgccgaaccaaaagaatttgcaccccgctgcgggcccacgtggttggggccctgccctggcagggtcatcctgtgctcggaggccatctcgggcacaggcccaccccgccccacccctccagaacacggctcacgcttacctcaaccatcctggctgcggcgtctgtctgaaccacgcgggggccttgagggacgcttgtctgtcgtgatggggcaagggcacaagtcctggatgttgtgtgtatcgagaggccaaaggctggtggcaagtgcacggggcacagcggagtctgtcctgtgacgcgcaagtctgagggtctgggcggcg 96 209218gattccctgcatcaactaagaaaagcctgttttctttatttcaaacttggtggcgaatgtgttgcgggtcctgttgggctgcttt_atctgtattgtctcctaaccctctagttttaattggacacttctttgctgttgcaatctatgccgtgtatttttgctttaagtcagaaccttggattacaaaacctcgagcccttctcagtagtggtgctgtattgtacaaagcgtgttctgtaatatttcctctaatttactcagaaatgaagtatatggttcattaagcttaaaggggaaccatttgtgaatgaatatttggaacttaccaagtcctaagagacttttggaagaggatatatatagcatagtaccataccacttata  97 209309tgcggaaatacctgaaatacagcaaaaatatcctggaccggcaagatcctccctctgtggtggtcaccagccaccaggc_atcccaggagaaaagaagaaactgaagtgcctggcctacgacttctacccagggaaaattgatgtgcactggactcgggccggcgaggtgcaggagcctgagttacggggagatgttcttcacaatggaaatggcacttaccagtcctgggtggtggtggcagtgcccccgcaggacacagccccctactcctgccacgtgcagcacagcagcctggcccagcccctcgtggtgccctgggaggccagctaggaagcaagggttggaggcaatgtgggatctcagacccagtagctgcccttcctgcctgatgtgggagctgaaccacagaaatcacagtcaatggatccacaaggcctgaggagcagtgtggggggacagacaggaggtggatttggagaccgaagactgggatgcctgtcttgagtagacttggacccaaaaaatcatctcaccttgagccca 98 209369gaagacttactgttggccatagttaattgtgtgaggaacacgccggcctttttagccgaaagactgcatcgagccttgaag_atggtattggaactgatgagtttactctgaaccgaataatggtgtccagatcagaaattgaccctttggacattcgaacagagttcaagaagcattatggctattccctatattcagcaattaaatcggatacttctggagactatgaaatcacactcttaaaaatctgtggtggagatgactgaaccaagaagataatctccaaaggtccacgatgggcttttccaacagctccaccttacttcttctcatactatttaagagaacaagcaaatataaacagcaacttgtgttcctaacagg  99 209752agagattcattgcagctcagcatggctcagaccagctcatacttcatgctgatctcctgcctgatgtttctgtctcagagcca_ataggccaagaggcccagacagagttgccccaggcccggatcagctgcccagaaggcaccaatgcctatcgctcctactgctactactttaatgaagaccgcgagacctgggttgatgcagatctctattgccagaacatgaattcgggcaacctggtgtctgtgctcacccaggccgagggtgcctttgtggcctcactgattaaggagagtggcactgatgacttcaatgtctggattggcctccatgaccccaaaaagaaccgccgctggcactggagcagtgggtccctggtctcctacaagtcctggggcattggagccccaagcagtgttaatcctggctactgtgtgagcctgacctcaagcacaggattccagaaatggaaggatgtgccttgtgaagacaagttctcct 100 209773ttttaccttggatgctgacttctaaatgaactgaagatgtgcccttacttggctgattttttttttccatctcataagaaaaatcag_s_atctgaagtgttaccaactagccacaccatgaattgtccgtaatgttcattaacagcatctttaaaactgtgtagctacctcacaaccagtcctgtctgtttatagtgctggtagtatcaccctttgccagaaggcctggctggctgtgacttaccatagcagtgacaatggcagtcttggctttaaagtgaggggtgaccctttagtgagcttagcacagcgggattaaacagtcctttaaccagcacagccagttaaaagatgcagcctcactgcttcaacgcagatt 101 209774agagagacacagctgcagaggccacctggattgcgcctaatgtgtttgagcatcacttaggagaagtcttctatttatttatt_x_attatttatttatttatttgtttgttttagaagattctatgttaatattttatgtgtaaaataaggttatgattgaatctacttgcacactctcccattatatttattgtttattttaggtcaaacccaagttagttcaatcctgattcatatttaatttgaagatagaaggtttgcagatattctctagtcatttgttaatatttcttcgtgatgacatatcacatgtcagccactgtgatagaggctgaggaatccaagaaaatggccagtaagatcaatgtgacggcagggaaatgtatgtgtgtctattttgtaactgtaaagatgaatgtcagttgttatttattgaaatgatttcacagtgtgtggtcaacatttctcatgttgaagctttaagaactaaaatgttctaaatatcccttggacattttatgtctttcttgtaagatactgccttgtttaatgttaattatgcagtgtttccctc 102 209792tcctctcgtggggtgtttacccctgtggctctgcccagcatccagctgtctacacccagatctgcaaatacatgtcctggat_s_atcaataaagtcatacgctccaactgatccagatgctacgctccagctgatccagatgttatgctcctgctgatccagatgcccagaggctccatcgtccatcctcttcctccccagtcggctgaactctccccttgtctgcactgttcaaacctctgccgccctccacacctctaaacatctcccctctcacctcattcccccacctatccccattctctgcctgtactgaagctgaaatgcaggaagtggtggcaaaggtttattccagagaagccaggaagccggtcatcacccagcctctgagagcagttactggggtcacccaacctgacttcctctgccactccccgctgtgtgactttgggcaagccaagtgccctctctgaacctcagtttcctcatctgcaaaatgggaacaatgacgtgcctacctcttagacatgttgtg 103 209875gaatggtgcatacaaggccatccccgttgcccaggacctgaacgcgccttctgattgggacagccgtgggaaggaca_s_atgttatgaaacgagtcagctggatgaccagagtgctgaaacccacagccacaagcagtccagattatataagcggaaagctaatgatgagagcaatgagcattccgatgtgattgatagtcaggaactttccaaagtcagccgtgaattccacagccatgaatttcacagccatgaagatatgctggttgtagaccccaaaagtaaggaagaagataaacacctgaaatttcgtatttctcatgaattagatagtgcatcttctgaggtcaattaaaaggagaaaaaatacaatttctcactttgcatttagtcaaaagaaaaaatgctttatagcaaaatgaaagagaacatgaaatgcttctttctcagtttattggttgaatgtgtatctatttgagtctggaaataactgatgtgtttgataattagtttagtttgtggcttcatggaa 104 209955acagctttccaaggtgacaaactcctctatgcagtgtatcgaaagctgggtgtttatgaagttgaagaccagattacagct_s_atgtcagaaaattcatagaaatgggtttcattgatgaaaaaagaatagccatatggggctggtcctatggaggatacgtttcatcactggcccttgcatctggaactggtcttttcaaatgtggtatagcagtggctccagtctccagctgggaatattacgcgtctgtctacacagagagattcatgggtctcccaacaaaggatgataatcttgagcactataagaattcaactgtgatggcaagagcagaatatttcagaaatgtagactatcttctcatccacggaacagcagatgataatgtgcactttcagaactcagcacagattgctaaagctctggttaatgcacaagtggatttccaggcaatgtggtactctgaccagaaccacggcttatccggcctgtccacgaaccacttatacacccacatgacccacttcctaaagcagtg 105 210052agtcaagtgaccagcctctgactgtgcctgtatctcccaaattctccactcgattccactgctaaactcagctgtgagctgc_s_atggataccgcccggcaatgggacctgctcttaacctcaaacctaggaccgtcttgctttgtcattgggcatggagagaacccatttctccagacttttacctacccgtgcctgagaaagcatacttgacaactgtggactccagttttgttgagaattgttttcttacattactaaggctaataatgagatgtaactcatgaatgtctcgattagactccatgtagttacttcctttaaaccatcagccggccttttatatgggtcttcactctgactagaatttagtctctgtgtcagcacagtgtaatctctattgctattgcccc106 210445gctttcaccggcaagttcgagatggagagtgagaagaattatgatgagttcatgaagctccttgggatctccagcgatgta_atatcgaaaaggcccgcaacttcaagatcgtcacggaggtgcagcaggatgggcaggacttcacttggtcccagcactactccgggggccacaccatgaccaacaagttcactgttggcaaggaaagcaacatacagacaatggggggcaagacgttcaaggccactgtgcagatggagggcgggaagctggtggtgaattccccaactatcaccagacctcagagatcgtgggtgacaagctggtggaggtctccaccatcggaggcgtgacctatgagcgcgtgagca 107 210511aaaggagcagtcgcacagacctttcctcatgctgcaggcccggcagtctgaagaccaccctcatcgccggcgtcggc_s_atggggcttggagtgtgatggcaaggtcaacatctgctgtaagaaacagttctttgtcagtttcaaggacatcggctggaatgactggatcattgctccctctggctatcatgccaactactgcgagggtgagtgcccgagccatatagcaggcacgtccgggtcctcactgtccttccactcaacagtcatcaaccactaccgcatgcggggccatagcccctttgccaacctcaaatcgtgctgtgtgcccaccaagctgagacccatgtccatgttgtactatgatgatggtcaaaacatcatcaaaaaggacattcagaacatgatcgtggaggagtgtgggtgctcatagagttgcccagc 108 210519cagaccttgtgatattccagttccccctgcagtggtttggagtccctgccattctgaaaggctggtttgagccttcatagga_s_atgagtttgcttacacttacgctgccatgtatgacaaaggacccttccggagtggcattctgcatttctgtggcttccaagtcttagaacctcaactgacatatagcattgggcacactccagcagacgcccgaattcaaatcctggaaggatggaagaaacgcctggagaatatttgggatgagacaccactgtattttgctccaagcagcctctttgacctaaacttccaggcaggattcttaatgaaaaaagaggtacaggatgaggagaaaaacaagaaatttggcctttctgtgggccatcacttgggcaagtccatcccaactgac 109 210559gtaacactctggtacagatctccagaagtattgctggggtcagctcgttactcaactccagttgacatttggagtataggca_s_atccatatttgctgaactagcaactaagaaaccacttttccatggggattcagaaattgatcaactcttcaggattttcagagctttgggcactcccaataatgaagtgtggccagaagtggaatctttacaggactataagaatacatttcccaaatggaaaccaggaagcctagcatcccatgtcaaaaacttggatgaaaatggcttggatttgctctcgaaaatgttaatctatgatccagccaaacgaatttctggcaaaatggcactgaatcatccatattttaat 110 210766ggttccatcaatggtgagcaccagcctgaatgcagaagcgctccagtatctccaagggtaccttcaggcagccagtgtg_s_atacactgctttaaactgcatttttctnaatgggctaaacccagatggtttcctaggaaatcacaggcttctgagcacagctgcatt 111 211429tactggaacctatgatctgaagagcgtcctgggtcaactgggcatcactaaggtcttcagcaatggggctgacctctccg_s_atgggtcacagaggaggcacccctgaagctctccaaggccgtgcataaggctgtgctgaccatcgacgagaaagggactgaagctgctggggccatgtttttagaggcc atacccatgtctatcccccccgaggtcaagttcaacaaaccctttgtcttcttaatgattgaacaaaataccaagtctcccctcttcatgggaaaagtggtgaatcccacccaaaaataactgcctctcgctcctcaacccctcccctccatccctggccccctccctggatgacattaaaga 112 211506gtgtgaaggtgcagttttgccaaggagtgctaaagaacttagatgtcagtgcataaagacatactccaaacctttccaccc_s_atcaaatttatcaaagaactgagagtgattgagagtggaccacactgcgccaacacagaaattattgtaaagctttctgatggaagagagctctgtctggaccccaaggaaaactgggtgcagagggttgtggagaa 113 212063attgtaaatcttttgtgtctcctgaagacttcccttaaaattagctctgagtgaaaaatcaaaagagacaaaagacatcttcg_ataatccatatttcaagcctggtagaattggcttttctagcagaacctttccaaaagttttatattgagattcataacaacaccaagaattgattttgtagccaacattcattcaatactgttatatcagaggagtaggagagaggaaacatttgacttatctggaaaagcaaaatgtacttaagaataagaataacatggtccattcacctttatgttatagatatgtctttgtgtaaatcatttgttttgagttttcaaagaatagcccattgttcattcttgtgctgtacaatgaccactgttattgttactttgacttttcagagcacaccc114 212070tccaaggactgagactgacctcctctggtgacactggcctagngcctgacactctcctaagaggttctctccaagccccc_ataaatagctccaggcgccctcggccgcccatcatggttaattctgtccaacaaacacacacgggtagattgctggcctgttgtaggtggtagggacacagatgaccgacctggtcactcctcctgccaacattcagtctggtatgtgaggcgtgcgtgaagcaagaactcctggagctacagggacagggagccatcattcctgcctgggaatcctggaagacttcctgcaggagtcagcgttcaatcttgaccttgaagatgggaaggatgttctttttacgtaccaattct 115 212190cgatgcaagtgtttctgttctgggaggtattggagggaaaaaancaagcaggatggctggaacactgtactgaggaatg_ataatagaaaggcttccagatgtctaaaagattctttaaactactgaactgttacctaggttaacaaccctgttgagtatttgctgtttgtccagttcaggaatttttgttttgttttgtctatatgtgcggcttttcagaagaaatttaatcagtgtgacagaaaaaaaaatgttttatggtagcttttactttttatgaaaaaaaaattatttgccttttaaattcttttcccccatccccctccaaagtcttgatagcaagcgttattttgggggtagaaacggtgaaatctctagcctctttgtgtttttgttgttgttgttgttgttgttttatataatgcatgtattcactaaaataaaatttaaaaaactcctgtcttgctagacaaggttgctgttgtgcagtgtgcctgtcactactggtctgtactccttggatttgc 116 212281tacagccaggcataacatatccactgtgtgcatagagggtctcttcacgttgatgcttggcattccatcagctttctctaagt_s_at ctttgctcaagttcaaccttaaaatgatgttag 117 212344ggaaaacacctcatttgaccttgccagctgaccttcaaaccctgcatttgaaccgaccaacattaagtccagagagtaaa_atcttgaatggaataacgacattccagaagttaatcatttgaattctgaacactggagaaaaaccgaaaaatggacggggcatgaagagactaatcatctggnaaaccgatttcagtggcgatggcatgacagagctagagctcgggcccagccccaggctgcagcccattcgcaggcacccgaaagaacttccccagtatggtggtcctggaaaggacatttttgaagatcaactatatcttcctgtgcattccgatggaatttcagttcatcagatgttcaccatggccaccgcagaacaccgaagtaattccagcatagcggggaagatgttgaccaaggtggagaagaatcacgaaaaggagaagtcacagcacctagaaggcagcgcctcctcttcactctcctctgattagatgaaactgttaccttacccta 118 212353aatatccttgttgtgtattaggtttttaaataccagctaaaggattacctcactgagtcatcagtaccctcctattcagctcccc_ataagatgatgtgtttttgcttaccctaagagaggttttcttcttatttttagataattcaagtgcttagataaattatgttttctttaagtgtttatggtaaactcttttaaagaaaatttaatatgttatagctgaatctttttggtaactttaaatctttatcatagactctgtacatatgttcaaattagctgcttgcctgatgtgtgtatcatcggtgggatgacagaacaaacatatttatgatcatgaataatgtgctttgtaaaaagatttcaagttattaggaagcatactctgttttttaatca 119 212354gtgtgcacacggagactcatcgttataatttactatctgccaagagtagaaagaaaggctggggatatttgggttggcttg_atgttttgattttttgcttgtttgtttgttttgtactaaaacagtattatcttttgaatatcgtagggacataagtatatacatgttatccaatcaagatggctagaatggtgcctttctgagtgtctaaaacttgacacccctggtaaatctttcaacacacttccactgcctgcgtaatgaagttttgattcatttttaaccactggaatttttcaatgccgtcattttcagttagatgattttgcactttgagattaaaatgccatgtctatttgattagtcttatttttttatttttacaggcttatcagtctcactgttggctgtcattgtgacaaagtcaaataaacccccaaggacgacacacagtatggatcacatattgtttgacattaagcttttgccagaaaatgttgcatgtgttttacctcgactt 120 212531caagagctacaatgtcacctccgtcctgtttaggaaaaagaagtgtgactactggatcaggacttttgttccaggttgcca_atgcccggcgagttcacgctgggcaacattaagagttaccctggattaacgagttacctcgtccgagtggtgagcaccaactacaaccagcatgctatggtgttcttcaagaaagtttctcaaaacagggagtacttcaagatcaccctctacgggagaaccaaggagctgacttcggaactaaaggagaacttcatccgcttctccaaatctctgggcctccctgaaaaccacatcgtcttccctgtcccaatcgaccagtgtatcgacggctgagtgcacaggtgccgccagntgccgcaccagcccgaacaccattgaggga 121 212942ccttcttgtccacggttttgttgagttttcactcttctaatgcaagggtctcacactgtgaaccacttaggatgtgatcactttca_s_atggtggccaggaatgttgaatgtctttggctcagttcatttaaaaaagatatctatttgaaagttctcagagttgtacatatgtttcacagtacaggatctgtacataaaagtttctttcctaaaccattcaccaagagccaatatctaggcattttcttggtagcacaaattttcttattgcttagaaaattgtcctccttgttatttctgtttgtaagacttaagtgagttaggtctttaaggaaagcaacgctcctctgaaatgcttgtcttttttctgagccgaaatagctggtcctttttcgggagttagatgtatagagtgtttgtatgtaaacatttcttgtaggcatcaccatg 122 213880caatatctgacaccactttggactcaagagactcagtaacgtattatcctgtttatttagcttggttttagctgtgttctctctgg_atataacccacttgatgttaggaacattacttctctgcttattccatattaatactgtgttaggtattttaagaagcaagttattaaataagaaaagtcaaagtattaattcttaccttctattatcctatattagcttcaatacatccaaaccaaatggctgttaggtagatttatttttatataagcatgtttattttgatcagatgttttaacttggatttgaaaaaatacatttatgagatgttttataagatgtgtaaatatagaactgtatttattactatagtaaaggttcagtaacattaaggaccatgataatgataataaaccttgtacagtggcatattctttgatttatattgtgtttctctgcccatt 123 213905cacaaaaccccagggacagcggtctccccagcctgccctgctcangccttgcccccaaacctgtactgtcccggagga_x_atggttgggaggtggaggcccagcatcccgcgcagatgacaccggttttcctagaagcccctcacccccactggcccactggtggctaggtctccccttatccttctggtccagcgcaaggaggggctgcttctgaggtcggtggctgtctttccattaaagaaacaccgtg 124 213975gaaataacccagacttaatcagaatgatncgattatgcccaatattaagtananaatataagaaaaggttatcttaaataga_s_attcaaggcaaaataccagctgatgaaggcatctgatgccttcatctgttcagtcatctccaaaaacagtaaaaataaccactttttgttgggcaatatgaaatttttaaaggagtagaataccaaatgatagaaacagactgcctgaattgagaattttgatttnttaaagtgtgtttctttctaaattgctgttccttaatttgattaatttaattcatgtattatgattaaatctgaggcagatgagcttacaagtattgaaataattactaattaatcacaaatgtgaagttatgcatgatgtaaaaaatacaaacattctaattaaaggctt125 214022tcaacaccctcttcttgaactggtgctgtctgggcttcatagcattcgcctactccgtgaagtctagggacaggaagatggt_s_attggcgacgtgaccggggcccaggcctatgcctccaccgccaagtgcctgaacatctgggccctgattctgggcatcctcatgaccattggattcatcctgttactggtattcggctctgtgacagtctaccatattatgttacagataatacaggaaaaacggggttactagtagccgcccatagcctgcaacctttgcactccactgtgcaatgctggccctgcacngctngggctgttgcccctgcccccttggtcctgcccctagatacagcagtttatacccacacacctgtctacagtgtcattcaata126 214235ggtgaggggatgacccctggagatgaagggaagaggtgaagccttagcaaaaatgcctcctcaccactccccaggag_ataatttttataaaaagcataatcactgattccttcactgacataatgtaggaagcctctgaggagaaaaacaaagggagaaacatagagaacggttgctactggcagaagcataagatctttgtacaatattgctggccctggttcacctgtttactgttatcacaata 127 214651gtgattcaaacttctgtgtactgggtgatgcacccattgtgattgtggaagatagaattcaatttgaactcaggttgtttatga_s_atggggaaaaaaacagttgcatagagtatagctctgtagtggaatatgtcttctgtataactaggctgttaacctatgattgtaaagtagctgtaagaatttcccagtgaaataaaaaaaaattttaagtgttctcggggatgcatagattcatcattttctccaccttaaaaatgcgggcatttaagtctgtccattatctatatagtcctgtcttgtctattgtatatataatctatatgattaaagaaaatatgcataatcagacaagcgtaatgcataatcagacaagcttgaatattgtttttgcaccagacgaacagtgaggaaattcggagctatacatatgtgcag 128 214974agtcagtgttgtcttaatatccttgataatgctgtaaagtttatttttacaaatatttctgtttaagctatttcacctttgtttggaaat_x_atccttcccttttaaagagaaaatgtgacacttgtgaaaaggcttgtaggaaagctcctccctttttttnctttaaacctttaaatgacaaacctaggtaattaatggttgtgaatttctatttttgctttgtttttaatgaacatttgtctttcagaataggattctgtgataatatttaaatggcaaaaacaaaacataattttgtgcaattaacaaagctactgcaagaaaaataaaacatttcttggtaaaaacgtatgtatttatatattatatatttatatataatatatattatatatttagcattgctgagctttttagatgcctattgtgtatcttttaaaggttttgaccattttgttatgagtaattacatatatattacattcactatattaaaattgtacttttttactatgtgnctcattggttcatagtctttattttgtcctttgaa 129 215091tatgtcgctgtccaagagaaggctgtggaagaacctatacaactgtgtttaatctccaaagccatatcctctccttccatga_s_atggaaagccgcccttttgtgtgtgaacatgctggctgtggcaaaacatttgcaatgaaacaaagtctcactaggcatgctgttgtacatgatcctgacaagaagaaaatgaagctcaaagtcaaaaaatctcgtgaaaaacggagntnggcctctcatctcagtggatatatccctcccaaaaggaaacaagggcaaggcttatcnttgtgtcaaaacggagagtcacccaactgtgtggaagacaagatgctctcnacagttgcagtacttacccttggctaagaact 130 217430agggcctaagggtgacagaggtgatgctggtcccaaaggtgctgatggctctcctggcaaagatggcgtccgtggtct_x_atgaccggccccattggtcctcctggccctgctggtgcccctggtgacaagggggaccccattcccgaggagctttatgag131 217523gagttattattatctcatagcgtatgttttcttgnacagccttgaataattttgattgacctctgggatgttattaaagcctaacgt_attccttctattctcacaaattttcgttatgacttcagaaggatcattaactctggtatctgtttgtttgcttgtatggcaccaataagcagatttcttctttctaatctatggattagtatagaccaggagaaggctaatacagagactatgaaacgggaataagtttttttaacgatatggcaaaattgtgactctgaaagatcattcatgtatattctaaaattaccacagtcataaaaagtcttggactttcatgaggaaatagcatagctagatatgaaaaaatatagaaaatcttcatcaatggaactattcttggggtagacactaatcatatgaaaagacaaatgctcattccctaagatagcctga 132 217867gcttctacgtcatcttcgacagagcccagaagagggtgggcttcgcagcgagcccctgtgcagaaattgcaggtgctgc_x_atagtgtctgaaatttccgggcctttctcaacagaggatgtagccagcaactgtgtccccgctcagtctttgagcgagcccattttgtggattgtgtcctatgcgctcatgagcgtctgtggagccatcctccttgtcttaatcgtcctgctgctgctgccgttccggtgtcagcgtcgcccccgtgaccctgaggtcgtcaatgatgagtcctctctggtcagacatcgctggaaatgaatagccaggcctgacctcaagcaaccatgaactcagctattaagaaaatcacatttccagggcagcagccgggatcgatggtggcgctttctcctgtgcccacccgtcttcaatctctgttctgctcccagatgccttctagattcactgtctt133 217996gaagtgggacgagcacatttctattgtcttcacttggatcaaaagcaaaacagtctctccgccccgcaccagatcaagta_atgtttggacatcaccctactgaaaacttgcgattcttcttagttttctgcatacttttcatcacgatgcaggaaacgatttcgagtcaagaagacttttatttatgaacctttgaaaggatcgtcttgtatggtgaattttctaggagcgatgatgtactgtaattttattttaatgtattttgatttatgattatttattagttttttttaaatgcttgttctaagacatttctgaatgtagaccattttccaaaaaggaaactttattttcaaaaacctaatccgtagtaattcctaatcttggagaataaaaaagggcggtggaggggaaaacattaagaatttattcattatttctcgagtactttcagaaagtctgacactttcattgttgtgccagctggtt 134218086ggcacagagcgcggagatgtaccactaccagcaccaacggcaacagatgctgtgcctggagcggcataaagagcca_atcccaaggagctggacacggcctcctcggatgaggagaatgaggacggagacttcacggtgtacgagtgcccgggcctggccccgaccggggaaatggaggtgcgcaaccctctgttcgaccacgccgcactgtccgcgcccctgccggcccccagctcaccgcctgcactgccatgacctggaggcagacagacgcccacctgctccccgacctcgaggcccccggggaggggcagggcctggagcttcccactaaaaacatgttttgatgctgtgtgcttttggctgggcctcgggctccaggccctgggaccccttgccagggagacccccgaacctttgtgccaggacacctcctggtcccctgcacctctcctgttcggtttagacccccaaactggagggggcatggagaaccgtagagcgcaggaacgggtgggtaatt 135 218211gccacaccttcgcgaaacctgtggtggcccaccagtcctaacgggacaggacagagagacagagcagccctgcact_s_atgttttccctccaccacagccatcctgtccctcattggctctgtgctttccactatacacagtcaccgtcccaatgagaaacaagaaggagcaccctccacatggactcccacctgcaagtggacagcgacattcagtcctgcactgctcacctgggtttactgatgactcctggctgccccaccatcctctctgatctgtgagaaacagctaagctgctgtgacttccctttaggacaatgttgtgtaaatctttgaaggacacaccgaagacctttatactgtgatcttttacccctttcactcttggctttcttatgttgc136 218507tggtgtatgctgtgctttcctcagcagtatggctctgacatctcttagatgtcccaacttcagctgttgggagatggtgatattt_attcaaccctacttcctaaacatctgtctggggttcctttagtcttgaatgtcttatgctcaattatttggtgttgagcctctcttccacaagagctcctccatgtttggatagcagttgaagaggttgtgtgggtgggctgttgggagtgaggatggagtgttcagtgcccatttctcattttacattttaaagtcgttcctccaacatagtgtgtattggtctgaagggggtggtgggatgccaaagcctgctcaagttatggacattgtggccaccatgtggct 137 218704gaatttctgctggactttatctgggcagaggaaggatggaatgaaggtagaaaaggcagaattacagctgagcgggga_atcaacaaagagttcttctctgggaaaagttttgtcttagagcaaggatggaaaatggggacaacaaaggaaaagcaaagtgtgacccttgggtttggacagcccagaggcccagctccccagtataagccatacaggccagggacccacaggagagtggattagagcacaagtctggcctcactgagtggacaagagctgatgggcctcatcagggtgacattcaccccagggcagcctgaccactcttggcccctcaggcattatcccatttggaatgtgaatgtggtggcaaagtgggcagaggaccccacctgggaacccttttccctcagttagtggggagactagcacctaggtacccacatgggtatttatatctgaaccagacagacgcttgaatcaggcactat 138 218796gagacagacttggcaagggaccccctggttctgagccagtagctgccatctggaaattcctcttttagcctctccttagag_atgtgaatgtgaatgaagcctcccaggcacccgctgaatttctgaggccttgcttaaagctcagaagtggtttaggcatttggaaaatctggttcacatcataaagaacttgatttgaaatgttttctatagaaacaagtgctaagtgtaccgtattatacttgatgttggtcatttctcagtcctatttctcagttctattattttagaacctagtcagttctttaagattataactggtcctacattaaaataatgcttctcgatgtcagattttacctgtttgctgctgagaacatctctgcctaatttaccaaagccagaccttcagttcaacatgcttccttagcttttcatagttgtctgacatttccatgaaaacaaaggaaccaactttgttttaaccaaactttgtttggttacagttttcaggggagcgtttcttccatgaca 139 218872catgtacgactcggacagcgacggccgcatcactctggaagaatatcgaaatgtaaagtggtcgaggagctgctgtcg_atggaaaccctcacatctagaaggagtccgctcgctccatcgccgacggggccatgatggaggcggccagcgtgtgcatggggcagatggagcctgatcaggtgtacgaggggatcaccacgaggacttcctgaagatctggcaggggatcgacattgagaccaagatgcacgtccgcttccttaacatggaaaccatggccctctgccactgacccaccgccacctccgcggagagactgcactttgcaatggggccgcctccccgcgtagctggagcagcccaggcccggcggacagcctcttcctgcagcgccggtacatagccaaggctcgtctgcgcaccttgtgtcttgtagggtatggtatgtgggacttcgct140 218963gaggaggaactgacgcagctacgccacgaactggagcggcagaacaatgaataccaagtgctgctgggcatcaaaa_s_atcccacctggagaaggaaatcaccacgtaccgacggctcctggagggagagagtgaagggacacgggaagaatcaaagtcgagcatgaaagtgtctgcaactccaaagatcaaggccataacccaggagaccatcaacggaagattagttctttgtcaagtgaatgaaatccaaaagcacgcatgagaccaatgaaagtttccgcctgttgtaaagtctattttcccccaaggaaagtccttgcacagacaccagtgagtgagttctaaaagatacccttggaattatcagactcagaaacttttatttttttttttctgtaacagtctcaccagacttctcataatgctcttaatatattgcacttttctaatcaaagtgcgagtttatgagggtaaagctctactttcctactg 141 218984aatcctgcaattctcaatcttgcactgcagcctcgacctcccaggctccagtgactctcccacctcagcctcctaagtagct_atgggagtacaggcgcgcaccaccacgcctagctgatttttgtatttttttgtagagacgggggtttggccatgttgccgaggctaactcctgggattacaggcatgagctgtgctggccgggtttttttttcttgatgtaaacgtgtacagctgttttattagttaaggtctaatttttactctaggtgccttttatgttcagaactctttccactggactggtatttgctcaaaaataaataatggtagagaagaaaactataaaaatggacaaggctttcttctatcagtagcgtttaccctttgtcaccagtggctttggtatttccatgtctggcattgcataaacttctctggtgtgaaaggataaatatgcctttctaaagttgtatatcaaaattgtatcaatttttattttctatgatttctagaaacaaatgtaataaatatttttaaaatctcctttctactggttatgta 142 219630ctcgttgcaatcgcctttgcagtcaaccacttctggtgccaggaggagccggagcctgcacacatgatcctgaccgtcg_atgaaacaaggcagatggagtcctggtgggaacagatggaaggtactcttcgatggcggccagtttcaggtccagtgagcatgagaatgcctatgagaatgtgcccgaggaggaaggcaaggtccgcagcaccccgatgtaaccttctctgtggctccaaccccaagactcccaggcacatgggatggatgtccagtgctaccacccaagccccctccttctttgtgtggaatctgcaatagtgggctgactccctccagccccatgccggccctacccgcccttgaagtatagccagccaaggttggagctcagaccgtgtctaggttggggctcg 143 219682gagagaaaacaatatagccccctacccttttcccaatcctttgccctcaaatcagtgacccaagggagggggggatttaa_s_atagggaaggagtgggcaaaacacataaaatgaatttattatatctaagctctgtagcaggattcatgtcgttctttgacagttctttctctttcctgtatatgcaataacaaggttttaaaaaaaaaaaaaaaaagtgagactattagacaaagtatttatgtaattatttgataactcagtaaataggtggaatatgaatgatggaaaattaaactttaatttattgacattgtacatagctctgtgtaaatagaattgcaactgtcaggttttgtgttcttgttttcctttagttgggtttatttccaggtcacagaattgctgttaacactagaaaacacacttcctgcaccaacaccaataccctttcaaaagagttgtctgcaacatttttgttttcttttttaatgtccaaaagtgggggaaagtgctatttcctattttcaccaaaattggggaaggagtgccactttccagc 144 219727ttagcactgaaagtctcttgccccaggaaaccccatcagtcccaggcagattgggacagctggtcaccttacgcaagag_atccaggctgaaacatcccctccatactcagctctttaacttttcttttcctttttcatcgggctctttcctaaaaagctgagctgtaaaatattttacatcgaggtataataaataatcatgtacatgttttaccaccacccaggtcaagacatagaatgtttcaacatttccatcaccccagaaactccccttgtacccccttccacttcgtctcccctagctcctagaagcaaccactgatgtgatttctaccaaatccagttttggtcctactaaatatactcttttgagactggcctcttttactcaccataatgcctttgtaattc145 219787tagctgtttcagagagagtacggtatatttatggtaattttatccactagcaaatcttgatttagtttgatagtgtgtggaatttta_s_atttttgaaggataagaccatgggaaaattgtggtaaagactgtttgtacccttcatgaaataattctgaagttgccatcagttttactaatcttctgtgaaatgcatagatatgcgcatgttcaactttttattgtggtcttataattaaatgtaaaattgaaaattcatttgctgtttcaaagtgtgatatctttcacaatagcctttttatagtcagtaattcagaataatcaagttcatatggataaatgcatttttatttcctatttctttagggagtgctacaaatgtttgtcacttaaatttcaagtttctgttttaatagttaactgactatagattgttttctatgccatgtatgtgccacttctgagagtagtaaatgactctttgctacatttta 146 219911gtgtaccagaattcggccatgagccgctacatactcatcatggggctcctgtacaaggtgctgggcgtcctcttctttgcc_s_atatagcctgcttcttatacaagcccctgtcggagtcttcagatggcctggaaacttgtctgcccagccagtcctcagcccctgacagtgccacagatagccagctccagagcagcgtctgaccaccgcccgcgcccacccggccacggcgggcactcagcatttcctgatgacagaacagtgccgttgggtgatgcaatcacacgggaacttctatttgacctgcaaccttctacttaacctgtggtttaaagtcggctgtgacctcctgtccccagagctgtacggccctgcagtgggtgggaggaacttgcataaatatatatttatggacacacagtttgcatcagaacgtgtttatagaatgtgttttatacccgatcgtgtgtggtgtgcgtgaggacaaactccgcaggggctgtgaatcccactgggagggcggtgggcctgcagcccgaggaaggcttgtgtgtcctcagttaa 147 219955gaagttgcaacattcgtttgataggaattccagaaaaggagagttatgagaatagggcagaggacataattaaagaaata_atattgatgaaaactttgcagaactaaagaaaggttcaagtcttgagattgtcagtgcttgtcgagtacctagtaaaattgatgaaaagagactgactcctagacacatcttggtgaaattttggaattctagtgataaagagaaaataataagggcttctagagagagaagagaaattacctaccaaggaacaagaatcaggttgacagcagacttatcactggacacactggatgctagaagtaaatggagcaatgtcttcaaagttctgctggaaaaaggctttaatcctagaatcctatatccagccaaaatggcatttgattttaggggcaaaacaaaggtatttcttagtattgaagaatttagagattatgttttgcatatgcccaccttgagagaattactggggaataatataccttagcacgccagggtgactaca 148 219956ttgcttgttccccggaggttgaagctacagtgagccttgattgtgtcactgcactccagcctgggcaacaggtaagactct_atgtctcaaaaaaaaaacaaaaaagaagaagaaaagtacttctacagccatgtcctattccttgatcatccaaagcacctgcagagtccagtgaaatgatatattctggctgggc 149 221577gacggcgtcaaggtcgtgggacgtgacacgaccgctgcggcgtcagctcagccttgcaagaccccaggcgcccgcg_x_atctgcacctgcgactgtcgccgccgccgtcgcagtcggaccaactgctggcagaatcttcgtccgcacggccccagctggagttgcacttgcggccgcaagccgccagggggcgccgcagagcgcgtgcgcgcaacggggaccactgtccgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaagaccgacaccggggtgtcgctccagacctatgatgacttgttagccaaagactgccactgca150 221729tggaattagaccatttggcttttgaactacataggaaaaatgacccaacatttcttagcatgagctacctcatctctagaag_atctgggatggacttactattcttgtttatattttagatactgaaaggtgctatgcttctgttattattccaagactggagataggcagggctaaaaaggtattattatttttcctttaatgatggtgctaaaattcttcctataaaattccttaaaaataaagatggtttaatcactaccattgtgaaaacataactgttagacttcccgtttctgaaagaaagagcatcgttccaatgcttgttcactgttcctctgtcatactgtatctggaatgctttgtaatacttgcatgcttcttagaccagaacatgtaggtccccttgtgtctcaatactttttttttcttaattgcatttgttggctctattttaattt 151 221730tagattccggtatatcgttcttcaagacacttgctctaagcggaatggaaatgtgggcaagactgtctttgaatatagaaca_atcagaatgtggcacgcttgcccatcatagatcttgctcctgtggatgttggcggcacagaccaggaattcggcgttgaaattgggccagtttgttttgtgtaaagtaagccaagacacatcgacaatgagcaccaccatcaatgaccaccgccattcacaagaactttgactgtttgaagttgatcctgagactcttgaagtaatggctgatcctgcatcagcattgtatatatggtcttaagtgcctggcctccttatccttcagaatatttattttacttacaatcctcaagttttaattgattttaaatatttttcaatacaacagtttaggtttaagatgaccaatgacaatgaccacctt 152 221731tacagcaccgatggccatgtaaataagatgatttaatgagatataatcctgtatataaantaaaaagtncncaatgagat_x_atngggcatatttaatgatgattatggagccttagaggtctttaatcattggttcnggctgcttttatgtagtttaggctggaaatggtttcacttgctctttgactgtcagcaagactgaagatggcttttcctggacagctagaaaacacaaaatcttgtaggtcattgcacctatctcagccataggtgcagtttgcttctacatgatgctaaaggctgcgaatgggatcctgatggaactaaggactccaatgtcgaactcttctttgctgcattcctttttcttcacttacaagaaaggcctgaatggaggacttttctgtaaccaggaacattttttaggggtcaaagtgctaataattaactcaaccaggtctactttttaatggctttcataacactaactcataaggttaccgatcaatgcatttcatacggatatagacctagggctctggagggtgggg 153 221922gtaaatagttaaccacagtagtctattaaggcattaatacttctctggacatgcgcgtttgagggtggaggggtcctgtaag_atgtgcttcatcgtctgtgattactgcttgggatgtgttctttggcagcttgtgagattactttacctagtgtttataaagtaggaagttaagtgaatcatagattagaatttaatactcttatggaaataattttttaacatcttaattgacaatggcgtttttttataca154 221923tagtccatactgagtgtcatcaacaatccagactgaagtcttctattttaatctcaatccccttttctgatttgccacccatgcct_s_atcttcaggctggaaacaatctcttggttccctaaagcactttcttctgactgctgtgattcagtgaaccttgccctttgctttctattacttgtgcatttgcctcacctgacaatgttttaaatcgcctttgtatctccttagctgctcaataa 155222449aatatgtcagtgcttgcttgatggaaacttctcttgtgtctgttgagactttaagggagaaatgtcggaatttcagagtcgcct_atgacggcagagggtgagcccccgtggagtctgcagagaggccttggccaggagcggcgggctttcccgaggggccactgtccctgcagagtggatgcttctgcctagtgacaggttatcaccacgttatatattccctaccgaaggagacaccttttcccccctgacccagaacagcctttaaatcacaagcaaaataggaaagttaaccacggaggcaccgagttccag156 222450ggctgggggagagccgggttcattccctgtcctcattggtcgtccctatgaattgtacgtttcagagaaattttttttcctatgt_atgcaacacgaagcttccagaaccataaaatatcccgtcgataaggaaagaaaatgtcgttgttgttgtttttctggaaactgcttgaaatcttgctgtactatagagctcagaaggacacagcccgtcctcccctgcctgcctgattccatggctgttgtgctgattccaatgctttcacgttggttcctggcgtgggaactgctctcctttgcagccccatttcccaagctctgttcaagttaaacttatgtaagctttccgtggcatgcggggcgcgcacccacgtccccgctgcgtaagactctgtatttggatgccaatccacaggcctgaagaaactgcttgttgtg 157 222549gtgagtatggcccaatgctttctgtggctaaacagatgtaatgggaagaaataaaagcctacgtgttggtaaatccaacag_atcaagggagatttttgaatcataataactcataaggtgctatctgttcagtgatgccctcagagctcttgctgttagctggcagctgacgctgctaggatagttagtttggaaatggtacttcataataaactacacaaggaaagtcagccaccgtgtcttatgaggaattggacctaataaattttagtgtgccttccaaacctgagaatatatgcttttggaagttaaaatttaaatggcttttgccacatacatagatcttcatgatgtgtgagtgtaattccatgtggatatcagttaccaaacattacaaaaaaattttatggcccaaaatgaccaacgaaattgttacaatagaatttatccaattttgatctttttatattcttctaccacacctggaaacagacc158 222608catggtttacatttactcagctactatatatgcagtgtggtgcacattttcacagaattctggcttcattaagatcattatttttgn_s_atctgcgtagcttacagacttagcatattagttttttctactcctacaagtgtaaattgaaaaatctttatattaaaaaagtaaactgttatgaagctgctatgtactaataatactttgcttgccaaagtgtttgggttttgttgttgtttgtttgtttgtttgtttttggttcatgaacaacagtgtctagaaacccattttgaaagtggaaaattattaagtcacctatcacctttaaacgcctttttttaaaattataaaatattgtaaagcagggtctcaacttttaaatacactttgaacttcttctctgaattattaaagttctttatgacctcatttataaacactaaattctgtcacctcctg 159 222696gccgctgtgctttcgtggaaatgacagttccttgttttttttgtttctgtttttgttttacattagtcattggaccacagccattcag_atgaactaccccctgccccacaaagaaatgaacagttgtagggagacccagcagcacctttcctccacacaccttcattttgangttcgggtttttgtgttaagttaatctgtacattctgtttgccattgttacttgtactatacatctgtatatagtgtacggcaaaagagtattaatccactatctctagtgcttgactttaaatcagtacagtacctgtacctgcacggtcacccgctccgtgtgtcgccctatattgagggctcaagctttcccttgttttttgaaaggggtttatgtataaatatattttatgcctttttattacaagtcttgt160 223062ggagtggtttaagagtgccaggcgaagggcaaactgtagatcgatctttatgctgttattacaggagaagtgacatacttt_s_atatatatgtttatattagcaaggtctgtttttaataccatatactttatatttctatacatttatatttctaataatacagttatcactgatatatgtagacacttttagaatttattaaatccttgaccttgtgcattatagcattccattagcaagagttgtaccccctccccagtcttcgccttcctctttttaagctgttttatgaaaaagacctagaagttcttgattcatttttaccattctttccataggtagaagagaaagttgattggttggttgtttttcaattatgccattaaactaaacatttctgttaaattaccctatcctttgttctctactgttttctttgtaatgtatgactacgagagtgatactttgctgaaaagtctttcccctattgtttatctattgtca 161223447ttcctgtgcaagtaccgaccatagagcaagaatcaagattctgctaactcctgcacagccccgtcctcttcctttctgctag_atcctggctaaatctgctcattatttcagaggggaaacctagcaaactaagagtgataagggccctactacactggcttttttaggcttagagacagaaactttagcattggcccagtagtggcttctagctctaaatgtttgccccgccatccctttccacagtatccttcttccctcctcccctgtctctggctgtctcgagcagtctagaagagtgcatctccagcctatgaaacagctgggtctttggccataagaagtaaagatttgaagacagaaggaagaaactcaggagtaagcttctagaccccttcagatctacacccttctgccctctctccattgcctgcaccccaccccagccactcaactcctgcttgtttttcctttggccatagg162 223970ggagctcagagatctaagctgctttccatcttttctcccagccccaggacactgactctgtacaggatggggccgtcctctt_atgcctccttctcatcctaatcccccttctccagctgatcaacccggggagtactcagtgttccttagactccgttatggataagaagatcaaggatgttctcaacagtctagagtacagtccctctcctataagcaagaagctctcgtgtgctagtgtcaaaagccaaggcagaccgtcctcctgccctgctgggatggctgtcactggctgtgcttgtggctatggctgtggttcgtgggatgttcagctggaaaccacctgccactgccagtgcagtgtggtggactggaccactgcccgctgctgccacctgacctgacagggaggaggctgagaactcagttttgtgaccatgacagtaatgaaaccagggtcccaaccaagaaatctaactcaaacgtcccact 163 224428gcaaagtttatttcagttcacatgtaaggtattgcaaataaattcttggacaattttgtatggaaacttgatattaaaaactagtc_s_attgtggttctttgcagtttcttgtaaatttataaaccaggcacaaggttcaagtttagattttaagcacttttataacaatgataagtgcctttttggagatgtaacttttagcagtttgttaacctgacatctctgccagtctagtttctgggcaggtttcctgtgtcagtattccccctcctctttgcattaatcaaggtatttggtagaggtggaatctaagtgtttgtatgtccaatttacttgcatatgtaaaccattgctgtgccattcaa 164 224646agacggccttgagtctcagtacgagtgtgcgtgagtgtgagccaccttggcaagtgcctg _x_at 165224915ggagtgtggtacttctcctagttgcagtcaggcttcatacgctnttgtcctgcccgttagagcagccagcgggtacagaat_x_atggattttggaagagggagtcaccactggacctccaaggaagccacgtgcagacatctacaaccttcgatctcctgacgagtttattgttggccaaaaccaggctttgattgaaccaggatgaatgcgggtgttggaagtagaatatatatatacatataaaattggttgggagccacgtgtaccagtgtgtgttgatcttggcttgattcagtctgccttgtaacagaaactggcgatggaatatgagaggagccctctggaaagaaaaggacagaccctgtgctttcatgaaagtgaagatctggctgaaccagttccacaaggttactgtatacatagcctgagtttaaaaggctgtgcccacttcaagaatgtcattgttagactttgaaatttctaactgcctacctgca 166 225295agggctgtaacagttgctgctagtattagggttccacatcattctaatgtatagtttcaagtcttaatagacaatctgaattcca_atctacatttcttttggctccaacattccttttagcttgaccagtctaatttaaaatgtgtttgttggaggtcattaacgttacttgtacaatgctgtcactgtgtgacatccatatgaattttggtatatatcaatcaatcaatcaatcannnncattgcattcaatcaatcagctgtgattgattnnnnatgcttagaaatactatagtaactagatgcagtgtgaattttttccattaacaaacaaacaagtcagtggcttaaatgtgattatggtcctgcaaggtgattcttgctaaaatatctaaacttttgttttgttttaactgaatcattttttaacttaaaaagctggaaaatatcaaatgctgttttttttttnncattgtcaacagtggtgtgtcattttatgtatgttcctaatgcttatggaactcctcca 167 225520ggaacgatgagcaccatgccaggactgcccacccggccctgatttatgacatagatcttgataccgaaacagaacaag_atttaaaggcttgttctaagtggacaaggctctcacaggacccgatgcagactcctgaaacagactactctttgcctttttgctgcagttggagaagaaactgaatttgaaaaatgtctgttatgcaatgctggagacatggtgaaataggccaaagatttcttcttcgttcaagatgaattctgttcacagtggagtatggtgttcggcaaaaggacctccaccaagactgaaagaaactaatttatttctgtttctgtggagtttccattatttctactgcttacactttagaatgtttattttatggggactaagggattangagtgtgaactaaaaggtaacattttccactctcaagttttctactttgtctttgaactgaa 168 225541gaaacacaaccaagacgcgaggatcnnnnnctntnnnnnnnnnnnnnctngcaagatggcgccgcagaaagac_ataggaagcccaagaggtcaacctggaggtttaatttggaccttactcatccagtagaagatggaatttttgattctggaaattttgagcaatttctacgggagaaggttaaagtcaatggcaaaactggaaatctcgggaatgttgttcacattgaacgcttcaagaataaaatcacagttgtttctgagaaacagttctctaaaaggtatttgaaataccttaccaagaaataccttaagaagaacaatcttcgtgattggcttcgagtggttgcatctgacaaggagacctacgaacttcgttacttccagattagtcaagatgaagatgaatcagagtcggaggactaggcaaaggctccccttacagggctttgcttatt 169 225664ggaacccagagctgctgtgtatttcgagcgggcagtttatcttttgctatacttattttcaattcaattacaccacgattcaaat_ataattcccctcctaaaaccaaaaaggagggaaacgtcaactccattgcaattacttatcttcctcttctatctctgttatacgccggggcatagaatgctcgtatacatctctttaacaaccacaaaccttaagccatgtagatgaagttagtgcatcaacgggatacagttccatattgccttaaacctccttgttttagacacactaacatttataccaaattgcagattattctgcagagagggaattgcatgtttgtgttgta 170 225681aattaatattcatcgcacttcttctgtggaaggactttgtgaaggaattggtgctggattagtggatgttgctatctgggttgg_atcacttgttcagattacccaaaaggagatgcttctactggatggaattcagtttctcgcatcattattgaagaactaccaaaataaatgctttaattttcatttgctacctctttttttattatgccttggaatggttcacttaaatgacattttaaataagtttatgtatacatctgaatgaaaagcaaagctaaatatgtttacagaccaaagtgtgatttcacactgtttttaaatctagcattattcattttgcttcaatcaaaagtggtttcaatattttttttagttggttagaatactttcttcatagtcacattctctcaacctataatttggaatattgttgtggtcttttgttttttctcttagtatagcatttttaaaaaaatataaaagctaccaatctttgtacaatttg171 225767ccgtgtgagcgatcgcggtgggttcgggccggtgtgacgcgtgcgccggccggccgccgaggggctgccgttctgc_atctccgaccggtcgtgtgtgggttgacttcggaggcgctctgcctcggaaggaaggaggtgggtggacgggggggcctggtggggttgcgcgcacgcgcgcaccggccgggcccccngccctgaacgcgaacgctcgaggtggccgcgcgcaggtgtttcctcgtaccgcagggccccctcccttccccaggcgtccctcggcgcctctgcgggcccgaggaggagcggctggcgggtggggggagtgtgacccaccctcggtgagaaaagccttctctagcgatctgagaggcgtgccttgggggtac 172 225799aaatgactggatggtcgctgctttttaagtttcaaattgacattccagacaagcggtgcctgagcccgtgcctgtcttcagat_atcttcacagcacagttcctgggaaggtggagccaccagcctctccntgaataactgggagatgaaacaggaagctctatgacacacttgatcgaatatgacagacacngaaaatcacgactcanccccctccagcacctctacctgttgcccgccgatcacagccggaatgcagctgaaagattccctggggcctggttccaaccgcccactgtggactctgaggcctctgcatttgcgggtggtctgcctgtgatattttggtcatgggctggtctg 173 225806tcttctcaggtcacttgtacacttggtttcctagtagaagctcacttgccacctctcaggggggtcccggattgcatccatca_atcaatcccaaaactngagttggggggaactggagggagcaaaacactgatttgatactagtcagtttgcttgaaactagttcacctaaagctagatctcttaaaaccaatttactgaaaacttgtttgcttaaagttaatgacttaatgactaatttgccaaaagctcaattcctattttggtgtgtttatatccatttaggtgtcctattcttttttgtcatgctttggatatttcaaggatttatatctattcatccaagagtacttctgagntattatcagcaacataaatttatcaaatttgcagcactttgtaaatgatgagattgcttcctacctttatggatgtcttt 174 225835aatgcattactttcacttaacactagacaccaggtcgaaaattttcaaggttatagtacttatttcaacaattcttagagatgct_atagctagtgttgaagctaaaaatagctttatttatgctgaattgtgatttttttatgccaaantttttttagttctaatcattgatgatagcttggaaataaataattatgccatggcatttgacagttcattattcctataagaattaaattgagtttagagagaatggtggtgttgagctgattattaacagttactgaaatcaaatatttatttgaacattattccatttgtattttaggtttccttttacattctttttatatgcattctgacattacatattttttaagactatggaaataatttaaagatttaagctctggtggatgattatctgctaagtaagtctgaaaatgtaatattttgataatactgtaatatacctgtcacacaaatgcttttctaatgttttaaccttgagtattgcagttgctgctttgtacagaggtt 175 226227gtacttctcctagttgcagtcaggcttcatacgctattgtcctgcccgttagagcagccagcgggtacagaatggattttgg_x_ataagagggagtcaccactggacctccaaggaagccacgtgcagacatctacaaccttcgatctcctgacgagtttattgttggccaaaaccaggctttgattgaaccaggatgaatgcgggtgttggaagtagaatatatatatacatataaaattggttgggagccacgtgtaccagtgtgtgttgatcttggcttgattcagtctgccttgtaacagaaactggcgatggaatatgagaggagccctctggaaagaaaaggacagaccctgtgctttcatgaaagtgaagatctggctgaaccagttccacaaggttactgtatacatagcctgagtttaaaaggctgtgcccacttcaagaatgtcattgttagactttgaaatttctaactgcctacctgca176 226237gaagaggagcaacatctatgccaaatactgtgcattctacaatggtgctaatctcagacctaaatgatactccatttaattta_ataaaaagagttttaaataattatctatgtgcctgtatttcccttttgagtgctgcacaacatgttaacatattagtgtaaaagcagatgaaacaaccacgtgttctaaagtctagggattgtgctataatccctatttagacaaaattaaccagaattcttccatgtgaaatggaccaaactcatattattgttatgtaaatacagagttttaatgcagtatgacatcccacaggggaaaagaatgtctgtagtgggtgactgttatcaaatattttatagaatacaatgaacggtgaacagactggtaacttgtttgagttcccatgacagatttgagacttg 177 226311aaacgacgcaaatctctgagctggggaccacttggagaaccggcttagtaacagtcctgatcttcgcaagccagcttctt_atctgcatctgaggggctcctggcgcccagaggaggcagacagatgtcttctagctgagtttctaaccgcatgatgagactcagaccttccgctgcactagaaaatctgcaacagtgtccctgagtcacttctccttagtgggcagactcgtgttagatttgtggaacccagctctctgatttactccttttggaaaacccatggaatttcatgtataaggctttcatttgtattttaaggtttttctgtttgttttgagtatatacatggtgctcaatagcaacatcttagcagatgaagcagtttatgattccactccctcctgtatgacaggtagccactatactgaatcaaggtgctgaactcaaatcacaaaattctggcttaccgatacaacaaccaatac178 226360gtcccactgctcacatacttatgtgctgctagtctctactcgaagttcgtgcaggactaatgcttttaaaatgaggtctaaaa_ataataattactagtcgagactattattctttaaacagaactgcctttttctactctttatgtaaactctttctattgtgttggtctaacnaggcactattttaaaattttttaatttttcccatagcacttaaaagagattttgtaaagaccttgctgtaaagattttgtaataaaatggtctaagggctctttttccaacattaccatttttaaaaaatgttttaaaagctagaagacaacttatgtatattctntatatgtatagcagcacatttcatttatggaaatatgttctcagaatatttatttactaatatatttatcttaagccatgtcttatgttgagagtgtgacattgttggaataatcattgaaaatgactaacacaagaccctgtaaatacatgataattgcacacagattttacatatttgcagaccaaaaatgatttaaaacaagttgtagtcttctatggttttg 179 226777tataaggtaactctttagtcctccatttagcacattttaaatcctccaaagaataagtatcatgtgattattttagctttacaaaaa_ataaaagttgaatggcgttttattttcatggcctataagcaggtaccttagtagggcagatataggaaaaacaaattagagcaaaacaaatcctctacaaatccaaggcaggaaaagtggtggcagagtgactcattctcctgtccctcccatcaggtcaaatcaggaggctgcagtgaatgcctgttctttgaatgtgtagcagttgttncctgtaactctttaaaacttggctataggctgtttagcacagtacagattaaagatacagttacgtaaacagcaaagtaattttatagtgcttcatccatttatcatgctttggtttgctaattttttcacatacctttttctatcacagtctgttgcttttgtacacatttctcatattggggttcgaca180 226835ggagtgtggtacttctcctagttgcagtcaggcttcatacgctattgtcctgcccgttagagcagccagcgggtacagaat_s_atggattttggaagagggagtcaccactggacctccaaggaagccacgtgcagacatctacaaccttcgatctcctgacgagtttattgttggccaaaaccaggctttgattgaaccaggatgaatgcgggtgttggaagtag 181227140ttaccctctatttaaatgctttgaaaaacagtgcattgacaatgggttgatatttttctttaaaagaaaaatataattatgaaagc_atcaagataatctgaagcctgttttattttaaaactttttatgttctgtggttgatgttgtttgtttgtttgtttctattttgttggttttttactttgttttttgttttgttttgttttgttttgcatactacatgcagttctttaaccaatgtctgtttggctaatgtaattaaagttgttaatttatatgagtgcatttcaactatgtcaatggtttcttaatatttattgtgtagaagtactggtaatttttttatttacaatatgtttaaagagataacagtttgatatgttttcatgtgtttatagcagaagttatttatttctatggcattccagcggatattttggtgtttgcgaggcatgcagtcaatattttgtacagttagtggacagtattcagcaacgcctgatagcttctttggcctt 182227174ctggcacaaccctgacattactaagtggaaatgttaggatttttcggcatcgcatgttagaatctctaaaatttaaacattcct_atgttaaatgactaaggtttgcttttatcaatatgaattctgaaggccaatatcataccattaactatgaaagcttttaattcctaaaaatagttttagagatattcaagcaatgctctcctaatatccatacgcaagtgtgtttatgacacaaattcactagtctgtttaaaaatgaattctttatattgactggtgttccacatatttcagtaatttctgttatgagaggacttgaaatagcaaattgccacacagttaactggatagaccangtacgtggtgatcataaccacttggtactacacccagaaactcaaaattgtctttctcctgatgagatatgggtgtccttttgtacgtctaggcctaggtaaccagtggagtgattatattagcaaatgtgtttgtatccagagtcttcc 183 227475ccaggcttcgtcttatttctactgtttttgtcgcaacttccattgatttatgtcccttccctcccccctaagtacatcagggaacc_attttccacactataaatgatatgactactgtttggggtttctgggcccccatccgtgtacgtatgtggcatttccaggtatgactgagtgtgagagacatgtcagaggctcttcagtgatttcttgctattgaccgatgcttcactgtgccaaaagagaaaaaaaatgttgggttttgtaattaaattatttatatatttttgaaacccgaattgaaaatgttgcaggcaacgggctacagctttattagtggttctctaactgtggtctccttgggccaagcaatttctttaaaggaaaagttgattatgtatgtggggtgccaggaccactgccttgaaagca 184 228303tagcccaaccctatcattttcatattatgaaactgagtccaggtaagtgaatctgtccaaggtcacccagcaaggtatcagt_atagccctgagggtaaggactctgataaggctcgggagggtcctggaaagcctgaggcggcaggaagagtgtgcagagttgagcgtgtctggaaggctgatccactgctgggcccacatcaaagcccccatggggagcagacccgactgcacatggctcttttgctggaagaagagcatngctgcgcagaggactaaaatttcatctgggaaggcttcttttgactgtcagtagcaggatgtcaccagatgagggtgctatgggaccacagctgtctttgttcccattgcaactcaaccctgcnggaggccgcctgcatccctgagagccttctggagcctacagaggagacattggccagccaaaaggaaaggagtggccagggtacgacct185 228653aattatcccttatcattccaaaaatgaaatgctgtgttaaatatctccagggcaaagtggtatgttgactgggacaaacgtta_atgaaattgtattgttcattgcacttgttgccctgttccccaagcttgtcaatgtttagagatactattcgggttgctaaagccattattcatagaaaatttctgcccctacagaagtgtgtgcatgggccttggaaaatctacatgtgtatatctgagtagcgaagcacagattcactctaattgaaagcagcagtttggttttgtaaatgtaattgcaattgacactttcttttccctttcagttattattttttttaaaggacgttatgagaaggcactatgaaaagcctaattggaatagcattatgaaccatgtaatgcatgcccatgcacactgtgatttgcaaacatatgtccgctcttcaat 186 228754ggtgggtgtcactacagacatgttctggcgtgttctccgagggatggagcatcctgttatatatttgacttcaaattgagatg_atttggcttcattttttttttttacccaattaatctcccaatccctagcaactgtgactctgtatttagcacaagagaaagctgagaatgtgggtcttgcctccttccagaaatatgtctggctcatcaggacatttttttaaaacttcaaaatatttttaagatattttaaacttttataaaaaaaaaatcaaccaacaagagacttttctgaggaggaacatttgtatttgaacaagatccttggtgtgtagttcagtcttgcagtatacaagcttttgtgtataaatgttttatgatatgattccctgtnttttgcaggggtttttttctcttttgctttttagataaatatgtatatcaatattttaaattcatctttgctttttttagaggagtttgtaatcaccttataac 187228915gaaaaaagctatcagctgtatgttaagagagactcttactaacatgttgtaaatattacaattcatgaaatgttattgtaagtct_atgtaacttaattttttccctgttttagttatacaggttggtttggaaatttgtgttttggcataaacaagtaaaatgtgcccattttatggtttccatgcttttgtaatcctaaaaatattaatgtctagttgttctatattataaccacatttgcgctctatgcaagcccttggaacagaacatactcatcttcatgtaggacctatgaaaattgtctatttttatctatatatttaaagttttctaaaaatgataaaaggttattacgaattttgttgtacaaaatctgtacaaaaatctgtttttacatcataatgcaagaattggaaatttttctatggtagcctagttatttgagcctggtttcaatgtgaga 188 229215gccgcggtggaaacgggcttggagctggccccataangggctngcggcttcctccgacgccgcccctccccacagct_attctcgactgcagtggggcggggggcaccaacacttggagatttttccggaggggagaggattttctaagggcacagagaatccattttctacacattaacttgagctgctggagggacactgctggcaaacggagacctatttttgtacaaagaacccttgacctggggcgtaataaagatgacctggacccctgcccccactatctgnngnnnnnnntgctggccaagatctggacacgagcagtccctgaggggcggggtccctggcgtgaggcccccgtgacagcccaccctggggtgggtttgtgggcactgctgctctgctagggagaagcctgtgtggggcacacctcttcaagggagcgtga 189 229802gacatgattgtctataatctcgctagccttgtactgtgtgtgcatagcaattacagggaagtaatctagctcctgactattatg_atttgaactatgtcgctgctttttacaaacttgtcttgatccaaagcagtcacaatgataaccctgcatatctgggaatcataagtcaactatgtatctctgtgtgtgtatatatatgtatgtatgtatctattttcaaactgtgatttaatatttaaatattcctactgccatttttgtgactgaaaaactacacatgaggaaacgtcttagaattttccaatagaggaaaaataacacttgggcaatctgtcatgtttcacaacagttctcatttttctcatgatttgtgtagcgtggaatgtgtttgctcaatgtgaagggttttcattgctcaatttctctgtgtaa 190 231766ggttccggctaacacattttctaagtcgccagtgctgcttacagtttgaatacatgaaaatcctgtttctnagatgtttgcgca_s_atcgtgcttattaggaaatgagtctgtatggaaatctcaccacagataatggttaacgaaccgggtcgacatcacaaaggagggtggagactctttttactaacttgaatgagacaaaagcagtggtgtcagtttataatcctgatgcatttcagtaataatgtagaaaaacattattttaaaaaagttccaacacacagccatgaggagccnnnnnnnnnntcagttttgaaagaggtgcataataaaactactaaccagaggagtctatgccatttt 191 231832gagtttcaactttaaatgttcactatgtcatttagtgtccanctttacggataggttgactatctaaataggcatttttagtcatta_ataaaaaaantctagtcaccaggaggatccctataactcaaaataacttgtttgtaaaagaaaatttgtttacttacccattagtaagttcctgcatattcattataagatggcaaatcaaacttttctaggatgaagacagcttatttttaagttgtatagtcttagttggtttagggtctcaattttaattaataaaatacttggtttttatttgcttgtccttttgaattcctgttttaataattttaaaatgagcacaaagaangttgaagttcagattaatctcttctgaatgatgtttttttcctctgtgatgagttgtttctg 192231941caccaagttacgtcaaagtctcaggagcagctccggtctccatagaggctgggtcagcagtgggcaaaacaacttccttt_s_atgctgggagctctgcttcctcctacagcccctcggaanncncnctcaagaacttcaccccttcagagacaccgaccatggacatcncaaccaaggggnccttccccaccagcanggaccctcttccttctgtccctccgactacaaccaacagcagccganngacgaacagcacntnnnnnaagatcacaacctcagcgaagaccacgatgaagcccc 193 232151gtacagcatgaaaggcttcctctacaagacactagtcaaagagttgagagctgcggtttctaatctttgtccattactccctt_atactccctatgagactgtggacctgtcacttggcctctctggtcttcagttttctcaccagtaaaacaaggaacttgaaccaaatgacctctagtgttccccttgggtttaaatgtctataaatgttcaatgactagaannnantgcgtttttctttattctttttgctttgagaaaagagaatgtgatttaagagtaataatttgaataccaattatccacattaaaattgtgtcctctatgtgtaaggcatagcacatttagcacacatacataagcacactaagcaccttacaaatatcctcatttattctttacataatcttttgaaatngattatgtaatacacacngttttnnaacaatnggtgacttccagctgtttaaaacaaactacagtatggtgcttgagtactgacttaggaggtcagcatnggtttcactaggagcttctcaaagcacgctgcc 194 232176gggatcactgggagaagccatggcattatcttcaggcaatttagtctgtcccaaataaaataaatccttgcatgtaaatcatt_atcaagggttatagtaatatttcatatactgaaaagtgtctcataggagtcctcttgcacatctaaaaaggctgaacatttaagtatcccgaattttcttgaattgctttccctatagattaattacaattggatttcatcatttaaaaaccatacttgtatatgtagttataatatgtaaggaatacattgtttataaccagtatgtacttcaaaaatgtgtattgtcaaacatacctaactttcttgcaataaatgcaaaagaaactggaacttgacaattataaatagtaatagtgaagaaaaaatagaaaggttgcaattatataggccatgggtggctcaaaactttgaa 195 232252ggacgatgaagccatcattgctgcttggagacgccggcaagaagaaaccaggaccaagctgcagaaaaggaggga_atggactgagctggggaaaatctgagaacactgaaagaaaccactcacgttagcatagggctcagggcacacgttgccaccactcatcgcaggatgaggatacagagaggatcttccagaggggcagagccaaaatgagagntaccaagcatnngggcannngaggtggagtagggaggaggcaaggagggggagaaccatcaatacgaatacgaggtccgaatgcggaccaactgataccattttctgttgctcagcgccctctaagctttggtgtttcacttaatgtatttgacagtgttcatcacaggctagagaggtgagcttggaaaagcactgtagtttgtcagagactccagtttacatccagaaaggccatgaacataggacacgcttctgtctgtagaggcttcatatgagacccagaaagtctatcctatggcaagtctgacctctcctggcaatgctcagttctgatt 196 232481gaagtccatcctttggtccaaagc atctggaagaggaagaagagaggaatgagaaagaaggaagtgatgcaaaacat_s_atctccaaagaagtcttttggaacaggaaaatcattcaccactcacagggtcaaatatgaaatacaaaaccacgaaccaatcaacagaatttttatccttccaagatgccagctcattgtacagaaacattttagaaaaagaaagggaacttcagcaactgggaatcacagaatacctaaggaaaaacattgctcagctccagcctgatatggaggcacattatcctggagcccacgaagagctgaagttaatggaaacattaatgtactcacgtccaaggaaggtattagtggaacagacaaaaaatgagtattttgaacttaaagctaatttacatgctgaacctgactatttagaagtcctggagcagcaaacatagatggagagtttgagggctttcgcagaaatgctgtgattctgttttaagtccataccttgtaaataagtgccttacgtgagtgtgtcatcaatcagaacctaagc197 234331accaagatggtgcaagttccctttgcagatggcgtgggcacacttgatttttattatgagtgaatgtaatctttctgtattttac_s_atcagagttacagcaattacctgaaaagtttcctaacattttaataatgttagggatttcgttttggttttagttgtcctcaagagacaacaggttcacagtaatttccatgatgttgggtgtggctaagctggggattggttctgttccccctgctcccgtgtagagaaaagctatatttatactgcattctttctcaactttcaggtaaaacaaactatgatttaaaaaaagaaaaaagaaaagacaggtacttttacttcaaagagtgctttgctacatttttatttaaaccaaaaatcaaataaaataaggaggggggctgggtatactttaaacaaaaccagtcctgaaatgctgttatt 198 235210ttcttgtccagctgttcacagttttatttttatatagatggtgatataaatatttccaaatgcatttgtaaacattctaaatattctca_s_atagtcatgttcaatgtttcctaaaccttcaattttggccaaagtccccaaacacatcattgccacactctgaagtagagaaagaaaatttaggggccagttctcaaggaacacaggtcctttatttttattttaactaagttgaagacccactcaaaaagctcttgtggttttatgttcttgacctttcaactggagtcctctcattcagcaggtggcccgtgagacacagaatac199 235976cagtgctgctgtgaactaaagtatgtcatttatgctcaaagtttaattcttcttcttgggatattttaaaaatgctactgagattct_atgctgtaaatatgactagagaatatattgggtttgctttatttcataggcttaattctttgtaaatctgaatgaccataatagaaatacatttcttgtggcaagtaattcacagttgtaaagtaaataggaaaaattattttatttttattgatgtacattgatagatgccataaatcagtagcaaaaggcacttctaaaggtaagtggtttaagttgcctcaanagagggacaatgtagctttattttacaagaaggcatagttagatttctatgaaatatttattctgtacagttttatatanttttggttcacaaaagtaattattcttgggtgcctttcaa 200 236894aaagtatattgtgctagcttgtctaagaataaacttnnatactgttgggggagggctgcacctgtcaagataacctgtcaat_atgtagtaggaaaacaggaggggacagtaacagaaaagcacgggaaaagatggcaaggttagttaaaatagaaaagtgctcagttcctcatacctgtaatcccagcagtttagggggccaaggaaggtgggtcacttgagcccaagagttcaaggccatcctgggcaatgtggcgaaagtgtctacaaaaaaatacaaaaagaggaagaaatgatatttcacaagtttgtatcatttgtcat 201 238017caaaaccacgattgtgtgccccttttttatnaaanctggnatgtttgaangttgtantacangctntncttctntgttgccaat_attctgnnacnnnnntnnnnannngaaaaaatagtagaagctattctacaagaaaaaatgtacttgtatatgccaaagttgttatacttcatgatgtttcttaaaagctttttgcccctcaagacaggactgcttatagctgactatttgggcatccttcatgcaatggatggctttgttgaccaaaagaagaagctctaaagaccaactctatggctaaggtcatctgatacacagtgttacataatgcgtacttcaatgaagaaaagtatttttgtctgacagtggaatatatctggagaccacaagtaccactcctattctgttatctgg 202 238021agccgttggtctttgaaatttcctgtgatgtgtttcaatctagatgcaaagaacatggaaaaatcaaagtgctcgagtggttt_s_ataaatatgttttgggtattcctgtttatagactataatacttttccaattaaaatcctcagttgtcacgcagaagaaggttaagctgtatttgattgccagttttactgaaaatgcttagtattttacagtatcaccaaatatattttgtttagccaaggtatagga203 238984acccaacaagagctgtgcggctccctgattcctcgccagtgttgctaccgcccttggctcttcttgcatggctggctcttga_atgacccctggaagctgatggaggcaacgtgagaagcacatggacatccgnccntgagcttgagaggcagaggcctgagttctagttacagccccagcagtaccagttgtgtggactgggagggaggcnatcacgtacatactccaagcctccaagcctgtttccccttctgacacaggatcttttgtggctggtatanagtgggcactcaataaatgctgtctggtcgtctggctggcatgcctnatgggcctgagaattgaatagaattacagtgatagaagcatgctggtattgtaagtggtttgtaagtgtgaggactaaattattattaaatagtaatcacatctaatcttggataaattagtaaaagcaagaatgggagcagtaaaaacctaagcaacccgaactaaaattttattgaattaattcaatttcttgtcatgtaacacaaccccaga 204 241031gtttctgtttcagtcacaaattagggttattgtgatgtgtatttatgatgaccnttgaacaaatgtgaagaatactgtgaattcta_attgactttatcaaaatcagccacatccaggagcttgcagttgttgaccaaatgaatgatgacatagagtagttcagatctatcatgtgctcttctatctaatcagtcaatatttccttggccctcaagccaacattcattttttatgtataaccttcttcatgattttgaaattttgatagggtaactgctaatgagttcacaaatgtagcactttaaaaggaaaataaatggagagtgaaaacaacttggctacgtataattgtgggt 205 37892_caacccattttgtgccacatgcaagttttgaataaggatggtatagaaaacaacgctgcatatacaggtaccatttaggnaatnnancngatgcctttntgggggcagaatcacatggcaaaagctttgaaaatcataaagatataagttggtgtggctaagatggaaacagggctgattcttgattcccaattctcaactctccttttcctatttgaatttctttggtgctgtagaaaacaaaaaaagaaaaatatatattcataaaaaatatggtgctcattctcatccatccaggatgtactaaaacagtgtgtttaataaattgtaattattttgtgtacagttctatactgttatctgtgtccatttccaaaacttgcacgtgtccctgaattcc 20660474_acagacttggcaagggaccccctggttctgagccagtagctgccatctggaaattcctcttttnnnnnnnnnnnnnnnatnnnnnnnnnnnnnnnnnctcccaggnacccgctgaatttctgaggccttgcttaaagctcagaagtggtttaggcatttggaaaatctggttcacatcataaagaacttgatttgaaatgttttctatagaaacaagtgctaagtgtnaccgtattatacttgatgttggtcatttctcagtcctatttctcagttctattattttagaacctagtcagttctttaagattataactggtcctacattaaaataatgcttctcgangtcagattttacctgtttgctgctgagaacatctctgcctaannnnnnnnnnnnnnnncttcagttcaacatgcttccttagcttttcatagttgtctgacatttccatgaaa

BIBLIOGRAPHY

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1. A method of screening for the onset or predisposition to the onset of a large intestine neoplasm or monitoring the progress of a neoplasm in an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from: (i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 205513_at; and/or (ii) TCN1 in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or group (ii) relative to control levels is indicative of a neoplastic large intestine cell or a cell predisposed to the onset of a neoplastic state.
 2. The method according to claim 1 wherein said control level is a non-neoplastic level.
 3. The method according to claim 1 wherein said neoplastic cell is an adenoma or an adenocarcinoma.
 4. The method according to claim 1 wherein said cell is a colorectal cell.
 5. The method according to claim 1 wherein said biological sample is a faecal sample, enema wash, surgical resection, tissue biopsy or blood sample.
 6. The method according to claim 1 wherein said level of expression is mRNA expression or protein expression.
 7. The method according to claim 1 wherein said biological sample is a fecal sample, enema wash, surgical resection, tissue biopsy or blood sample.
 8. The method according to claim 1 wherein said individual is a human. 